Pharmaceutical compositions and methods of treating cardiovascular diseases

ABSTRACT

Provided herein is a pharmaceutical composition comprising two or more compounds, wherein each compound is independently a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, a histamine H1-receptor agonist, a histamine H2-receptor agonist, a histamine H3-receptor antagonist, or a β2-adrenoreceptor agonist. Also provided herein is a method of treating, preventing, or ameliorating a cardiovascular disease in a subject, comprising administering to the subject in need thereof two or more compounds, wherein each compound is independently a phosphodiesterase inhibitor, an adenosine receptor antagonist, a calcium channel blocker, a histamine H1-receptor agonist, a histamine H2-receptor agonist, a histamine H3-receptor antagonist, or a β2-adrenoreceptor agonist.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of divisional applicationSer. No. 16/353,675, filed on Mar. 14, 2019, which is directed tonon-provisional application Ser. No. 15/973,132, filed on May 7, 2018,directed to U.S. Provisional Application No. 62/503,902, filed May 9,2017, and U.S. Provisional Application No. 62/652,812, filed Apr. 4,2018, the disclosure of each of which is incorporated herein byreference in its entirety.

FIELD

Provided herein is a pharmaceutical composition comprising two or morecompounds, wherein each compound is independently a phosphodiesteraseinhibitor, an adenosine receptor antagonist, a calcium channel blocker,a histamine H₁-receptor agonist, a histamine H₂-receptor agonist, ahistamine H₃-receptor antagonist, or a β₂-adrenoreceptor agonist. Alsoprovided herein is a method of treating, preventing, or ameliorating acardiovascular disease in a subject, comprising administering to thesubject two or more compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

BACKGROUND

Cardiovascular diseases are a class of diseases that involve the heartor blood vessels. Mendis et al., Global Atlas on Cardiovascular DiseasePrevention and Control—World Health Organization, World HeartFederation, and World Stroke Organization 2011. Cardiovascular diseasesinclude coronary artery diseases such as angina and myocardialinfarction (commonly known as heart attack), stroke, hypertensive heartdisease, rheumatic heart disease, cardiomyopathy, cardiac arrhythmia,congenital heart disease, valvular heart disease, carditis, aorticaneurysms, peripheral artery disease, and venous thrombosis. Id.; Lancet2014, 385, 117-171. Cardiovascular diseases are the leading cause ofdeath globally. Mendis et al., Global Atlas on Cardiovascular DiseasePrevention and Control—World Health Organization, World HeartFederation, and World Stroke Organization 2011. In 2013, cardiovasculardiseases resulted in 17.3 million deaths (31.5%), up from 12.3 million(25.8%) in 1990. Lancet 2014, 385, 117-171. In the United States, 11% ofpeople between 20 and 40 have a cardiovascular disease, while 37%between 40 and 60, 71% of people between 60 and 80, and 85% of peopleover 80 have a cardiovascular disease. Go et al., Circulation 2013, 127,e6-e245.

One form of cardiac arrhythmia is bradycardia, a slow heart ratecondition, which can cause fainting, dizziness, malaise, generalweakness, excessive fatigue, chest pain, or failing memory. With noapproved drug therapy available for effective treatment of chronicbradycardia, a cardiac pacemaker must often be installed into a patientto sustain his/her life. Although several studies had investigatedpotential therapy with some drugs (Alboni et al., Am. J. Cardiol. 1990,65, 1037-1039; Ling et al., Ann. Pharmacother. 1998, 32, 837-839;Benditt et al., Am. J. Cardiol. 1983, 52, 1223-229), the adverse sideeffects at therapeutic doses prevent routine, long-term use of thesepreviously tested drug candidates. Thus, currently, there is no approveddrug worldwide for treating bradycardia. The treatment of choice forchronic, symptomatic bradycardia is limited to the implantation of acardiac pacemaker. It is estimated that the United States and Europe, aswell as other advanced countries, have a rate of pacemaker implantationof about 50-60/100,000 people per annum. A worldwide survey published in2009 indicates that approximately one million pacemaker implantations(approximately 740,000 new implants) were performed in the 61 countriesresponding to the survey. By 2028, it is estimated that over 700,000 newpacemaker implantations will be done in the US alone. The 10-yearprevalence (US 1999-2008) of clinically defined bradycardia (abnormallyslow heart rate, RPR (resting pulse rate)<60 beats/min) is 15.2% formale adults and 6.9% for females. US National Health Statistics Reports2011, 41, 1-16. Since the human pulse rate is inversely associated withage and the aged population is increasing worldwide, there will be acontinually increasing number of patients with bradycardia requiringpacemaker implants. Furthermore, due to the adverse side effects andhigh cost of pacemakers, many bradycardia patients either cannot orelect not to have a pacemaker implanted even when needed from a medicalperspective.

As noted, current medical treatment for bradycardia requires a surgicalinsertion of a cardiac pacemaker. The first use of a buried cardiacpacemaker occurred in Sweden in 1958. Since then, this approach for thetreatment of abnormal cardiac rhythms has gradually spread all over theworld. In recent years, the quality of pacemakers has improved; and as aresult, the use of pacemakers to treat bradycardia has greatlyincreased. Unfortunately, cardiac pacemakers have some limitations. Forexample, pacemakers require a surgical procedure for implantation in thehuman body, and infections requiring device removal do occur with afinite frequency. In addition, pacemakers may not provide a normalphysiological heart rate response to exertion or a normal contractilepattern. Because of inadequate or inappropriate heart rate responseduring exertion, patients may develop significant symptoms related toinadequate cardiac output. In addition, pacing the right ventricle only(as occurs with single or dual chamber pacemakers) may lead tosignificant left ventricular dysfunction and worsening of heart failurein some patients. Left ventricular failure associated with rightventricular pacing may be ameliorated by implantation of abi-ventricular pacemaker, but this procedure is time consuming,difficult, and not always possible due to technical issues. As has beenrecently observed, pacemakers and pacemaker leads may fail and aresubject to periodic recalls by sovereign regulatory agencies such as theFDA. Finally, the costs of pacemaker implantation, replacement andfollow up are high. Nonetheless, in the absence of a reasonablealternative treatment for bradycardia, doctors and patients usually optto use a pacemaker when it is necessary. Furthermore, many bradycardiapatients delay or forgo the pacemaker surgery due to the potentialcomplications discussed herein and choose to live with bradycardia andthe associated potentially fatal medical risks instead. Therefore, thereis an unmet need for an effective drug therapy for treating bradycardia.

SUMMARY OF THE DISCLOSURE

To overcome the deficiencies associated with current treatments ofbradycardia, provided herein are methods and pharmaceutical compositionsuseful for treating bradycardia and associated cardiovascular diseases.

Provided herein is a pharmaceutical composition comprising (a) two ormore compounds, wherein each compound in the pharmaceutical compositionis independently (i) a phosphodiesterase inhibitor or an adenosinereceptor antagonist, (ii) a calcium channel blocker, (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist, or (iv) a β₂-adrenoreceptor agonist; and (b) apharmaceutically acceptable excipient.

Also provided herein is a pharmaceutical composition comprising (a)three or more compounds, wherein each compound in the pharmaceuticalcomposition is independently (i) a phosphodiesterase inhibitor or anadenosine receptor antagonist, (ii) a calcium channel blocker, (iii) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist, or (iv) a β₂-adrenoreceptor agonist;and (b) a pharmaceutically acceptable excipient.

Furthermore provided herein is a pharmaceutical composition comprising(i) a phosphodiesterase inhibitor or an adenosine receptor antagonist;(ii) a calcium channel blocker; (iii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist; or(iv) a β₂-adrenoreceptor agonist.

Additionally provided herein is a pharmaceutical composition comprising(i) a phosphodiesterase inhibitor or an adenosine receptor antagonist;(ii) a calcium channel blocker; and (iii) a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, or a histamine H₃-receptorantagonist.

Provided herein is a pharmaceutical composition comprising (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) acalcium channel blocker; and (iii) a β₂-adrenoreceptor agonist.

Provided herein is a pharmaceutical composition comprising (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist; and (iii) a β₂-adrenoreceptor agonist.

Provided herein is a pharmaceutical composition comprising (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) acalcium channel blocker; (iii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist;and (iv) a β₂-adrenoreceptor agonist.

Provided herein is a pharmaceutical composition comprising (a) two ormore compounds, wherein each compound is independently (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist, in oneembodiment, theophylline, aminophylline, or an isotopic variant thereof,in the amount ranging from about 5 to about 90% or from about 5 to about35% by weight; (ii) a calcium channel blocker, in one embodiment,nifedipine or an isotopic variant thereof, in the amount ranging fromabout 1 to about 20% or from about 1 to about 5% by weight; (iii) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist, in one embodiment, betahistinedihydrochloride or an isotopic variant thereof, in the amount rangingfrom about 0.1 to about 20% or from about 0.5 to about 5% by weight; or(iv) a β₂-adrenoreceptor agonist, in one embodiment, albuterol,levalbuterol hydrochloride, or an isotopic variant thereof, in theamount ranging from about 0.01 to about 5% or from about 0.1 to about0.5% by weight; and (b) a pharmaceutically acceptable excipient.

Provided herein is a pharmaceutical composition comprising (a) three ormore compounds, wherein each compound is independently (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist, in oneembodiment, theophylline, aminophylline, or an isotopic variant thereof,in the amount ranging from about 5 to about 90% or from about 5 to about35% by weight; (ii) a calcium channel blocker, in one embodiment,nifedipine or an isotopic variant thereof, in the amount ranging fromabout 1 to about 20% or from about 1 to about 5% by weight; (iii) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist, in one embodiment, betahistinedihydrochloride or an isotopic variant thereof, in the amount rangingfrom about 0.1 to about 20% or from about 0.5 to about 5% by weight; and(iv) a β₂-adrenoreceptor agonist, in one embodiment, albuterol,levalbuterol hydrochloride, or an isotopic variant thereof, in theamount ranging from about 0.01 to about 5% or from about 0.1 to about0.5% by weight; and (b) a pharmaceutically acceptable excipient.

Provided herein is a method of treating, preventing, or ameliorating acardiovascular diseases in a subject, comprising administering to thesubject in need thereof a therapeutically effective amount of two ormore compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

Provided herein is a method of treating, preventing, or amelioratingsymptomatic sinus bradycardia in a subject, comprising administering tothe subject in need thereof a therapeutically effective amount of two ormore compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

Provided herein is a method of treating, preventing, or amelioratingstroke in a subject, comprising administering to the subject in needthereof a therapeutically effective amount of two or more compounds,wherein each compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

Provided herein is a method of treating, preventing, or amelioratingcerebral vascular thrombosis in a subject, comprising administering tothe subject in need thereof a therapeutically effective amount of two ormore compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

Provided herein is a method of treating, preventing, or amelioratingabnormal heart rhythm in a subject, comprising administering to thesubject in need thereof a therapeutically effective amount of two ormore compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

Provided herein is a method of increasing heart rate in a subject,comprising administering to the subject in need thereof an effectiveamount of two or more compounds, wherein each compound is independentlya phosphodiesterase inhibitor, an adenosine receptor antagonist, acalcium channel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

Provided herein is a method of increasing cardiac output in a subject,comprising administering to the subject in need thereof an effectiveamount of two or more compounds, wherein each compound is independentlya phosphodiesterase inhibitor, an adenosine receptor antagonist, acalcium channel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

Provided herein is a method of increasing cerebral blood flow in asubject, comprising administering to the subject in need thereof aneffective amount of two or more compounds, wherein each compound isindependently a phosphodiesterase inhibitor, an adenosine receptorantagonist, a calcium channel blocker, a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, a histamine H₃-receptor antagonist, ora β₂-adrenoreceptor agonist.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inmedicinal chemistry, biochemistry, biology, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “subtherapeutically effective amount” of a compound refers to adose lower than the amount that is effective when the compound isadministered alone.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to a pharmaceuticallyacceptable material, composition, or vehicle, such as a liquid or solidfiller, diluent, solvent, or encapsulating material. In one embodiment,each component is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients of a pharmaceutical formulation,and suitable for use in contact with the tissue or organ of a subject(e.g., a human or an animal) without excessive toxicity, irritation,allergic response, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 22nd ed.; Allen Ed.: Philadelphia,Pa., 2012; Handbook of Pharmaceutical Excipients, 7th ed.; Rowe et al.,Eds.; The Pharmaceutical Press and the American PharmaceuticalAssociation: 2012; Handbook of Pharmaceutical Additives, 3rd ed.; Ashand Ash Eds.; Gower Publishing Company: 2007; PharmaceuticalPreformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: BocaRaton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient,” “active pharmaceutical ingredient,”“API,” and “active substance” are used interchangeably herein inreference to a compound, which is administered, alone or in combinationwith one or more pharmaceutically acceptable excipients, to a subjectfor treating, preventing, or ameliorating one or more symptoms of adisorder, disease, or condition. As used herein, “active ingredient,”“active pharmaceutical ingredient,” “API,” and “active substance” may bea metabolite and/or an isotopic variant and/or an optically activeisomer of a compound described herein.

The term “isotopically enriched” or “isotopic variant” refers to acompound that contains an unnatural proportion of an isotope at one ormore of the atoms that constitute such a compound. In certainembodiments, an isotopically enriched compound contains unnaturalproportions of one or more isotopes, including, but not limited to,hydrogen (¹H), deuterium (²H), tritium (³H), carbon-11 (¹¹C), carbon-12(¹²C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14(¹⁴N), nitrogen-15 (¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16(¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18(¹⁸F), phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P),sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37(³⁷Cl), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I),iodine-125 (¹²⁵I), iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131(¹³¹I). In certain embodiments, an isotopically enriched compound is ina stable form, that is, non-radioactive. In certain embodiments, anisotopically enriched compound contains unnatural proportions of one ormore isotopes, including, but not limited to, hydrogen (¹H), deuterium(²H), carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17(¹⁷F), phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34(³⁴S), sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an isotopically enriched compound is in an unstable form,that is, radioactive. In certain embodiments, an isotopically enrichedcompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, as example, or any carboncan be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, or anyoxygen can be ¹⁸O, as example, where feasible according to the judgmentof one of skill.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, an optically active compound comprisesabout 95% or more of one enantiomer and about 5% or less of the otherenantiomer based on the total weight of the enantiomeric mixture inquestion.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the compound about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of thecompound, R and S.

The term “isotopic enrichment” refers to the percentage of incorporationof a less prevalent isotope (e.g., D for hydrogen) of an element at agiven position in a molecule in the place of a more prevalent isotope(e.g., ¹H for hydrogen) of the element. As used herein, when an atom ata particular position in a molecule is designated as a particular lessprevalent isotope, it is understood that the abundance of that isotopeat that position is substantially greater than its natural abundance.

The term “isotopic enrichment factor” refers the ratio between theisotopic abundance in an isotopically enriched compound and the naturalabundance of a specific isotope.

The term “hydrogen” or the symbol “H” refers to the composition ofnaturally occurring hydrogen isotopes, which include protium (¹H),deuterium (²H or D), and tritium (³H), in their natural abundances.Protium is the most common hydrogen isotope having a natural abundanceof more than 99.98%. Deuterium is a less prevalent hydrogen isotopehaving a natural abundance of about 0.0156%.

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156% on average, deuterium enrichment at anyposition in a compound synthesized using non-enriched starting materialsis about 0.0156% on average. As used herein, when a particular positionin an isotopically enriched compound is designated as having deuterium,it is understood that the abundance of deuterium at that position in thecompound is substantially greater than its natural abundance (0.0156%).

The term “carbon” or the symbol “C” refers to the composition ofnaturally occurring carbon isotopes, which include carbon-12 (¹²C) andcarbon-13 (¹³C) in their natural abundances. Carbon-12 is the mostcommon carbon isotope having a natural abundance of more than 98.89%.Carbon-13 is a less prevalent carbon isotope having a natural abundanceof about 1.11%.

The term “carbon-13 enrichment” or “¹³C enrichment” refers to thepercentage of incorporation of carbon-13 at a given position in amolecule in the place of carbon. For example, carbon-13 enrichment of10% at a given position means that 10% of molecules in a given samplecontain carbon-13 at the specified position. Because the naturallyoccurring distribution of carbon-13 is about 1.11% on average, carbon-13enrichment at any position in a compound synthesized using non-enrichedstarting materials is about 1.11% on average. As used herein, when aparticular position in an isotopically enriched compound is designatedas having carbon-13, it is understood that the abundance of carbon-13 atthat position in the compound is substantially greater than its naturalabundance (1.11%).

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which are present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The phrase “an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof” has the samemeaning as the phrase “(i) an isotopic variant of the compoundreferenced therein; or (ii) a pharmaceutically acceptable salt, solvate,hydrate, or prodrug of the compound referenced therein, or (iii) apharmaceutically acceptable salt, solvate, hydrate, or prodrug of anisotopic variant of the compound referenced therein.”

Pharmaceutical Compositions

In an embodiment, provided herein are pharmaceutical compositions usefulfor treating symptomatic sinus bradycardia. In some embodiments,provided herein is a pharmaceutical composition comprising two or morecompounds, wherein each compound is independently a phosphodiesteraseinhibitor, an adenosine receptor antagonist, a calcium channel blocker,a histamine H₁-receptor agonist, a histamine H₂-receptor agonist, ahistamine H₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

The present disclosure discloses a surprising benefit associated with acombination of two or more active pharmaceutical ingredients (API)provided herein for treating a cardiovascular disease, e.g.,bradycardia. Specifically, without being bound by theory, thecombination of two or more APIs provided herein utilizes a secondarytherapeutical effect (e.g., an undesired side effect associated with thecurrently approved indication(s)) of each API at a subtherapeuticallyeffective amount to elicit/enhance a desired therapeutical effect, suchas increased heart rate and/or increased cardiac output; and suchdesired therapeutical effect is useful to treat a cardiovasculardisease, such as heart failure associated with abnormal cardiac outputor bradycardia. Without being bound by theory, the combination of two ormore APIs provided herein takes advantage of counteracting adverse sideeffects of each API such as increased/decreased oxygen consumption andincreased/reduced blood pressure. As a result, the APIs when taken in acombination provided herein achieve desired therapeutical effects,including increased heart rate and cardiac output in patients withminimized adverse side effects or without undesired adverse side effectssuch as increased oxygen consumption or elevated blood pressureassociated with an API when taken alone. The combination provided hereincombines two or more APIs that all possess the same desired secondarytherapeutical effects of increasing heart rate and cardiac output, wherethe undesired side effects of one API are counteracted by the sideeffects from another API in the combination. Furthermore, by reducingthe amount of each API to a subtherapeutically effective amount, theundesired adverse side effects of each API are further reduced.

In one embodiment, provided herein is a pharmaceutical compositioncomprising two compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; and(ii) a calcium channel blocker. In another embodiment, thepharmaceutical composition comprises (i) a phosphodiesterase inhibitoror an adenosine receptor antagonist; and (ii) a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, or a histamine H₃-receptorantagonist. In yet another embodiment, the pharmaceutical compositioncomprises (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist; and (ii) a β₂-adrenoreceptor agonist. In yet anotherembodiment, the pharmaceutical composition comprises (i) a calciumchannel blocker; and (ii) a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist. In yetanother embodiment, the pharmaceutical composition comprises (i) acalcium channel blocker; and (ii) a β₂-adrenoreceptor agonist. In stillanother embodiment, the pharmaceutical composition comprises (i) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist; and (ii) a β₂-adrenoreceptor agonist.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising three compounds, wherein each compound isindependently a phosphodiesterase inhibitor, an adenosine receptorantagonist, a calcium channel blocker, a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, a histamine H₃-receptor antagonist, ora β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) acalcium channel blocker; and (iii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist. Inanother embodiment, the pharmaceutical composition comprises (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; (ii) acalcium channel blocker; and (iii) a β₂-adrenoreceptor agonist. In yetanother embodiment, the pharmaceutical composition comprises (i) acalcium channel blocker; (ii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist;and (iii) a β₂-adrenoreceptor agonist. In yet another embodiment, thepharmaceutical composition comprises (i) a phosphodiesterase inhibitoror an adenosine receptor antagonist; (ii) a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, or a histamine H₃-receptorantagonist; and (iii) a β₂-adrenoreceptor agonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising four compounds, wherein each compound isindependently a phosphodiesterase inhibitor, an adenosine receptorantagonist, a calcium channel blocker, a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, a histamine H₃-receptor antagonist, ora β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition provided hereincomprises: (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist; (ii) a calcium channel blocker; (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist; and (iv) β₂-adrenoreceptor agonist.

In certain embodiments, the phosphodiesterase inhibitor or adenosinereceptor antagonist is a solid. In certain embodiments, thephosphodiesterase inhibitor or adenosine receptor antagonist is acrystalline solid. In certain embodiments, the phosphodiesteraseinhibitor or adenosine receptor antagonist is an amorphous solid.

In certain embodiments, the calcium channel blocker is a solid. Incertain embodiments, the calcium channel blocker is a crystalline solid.In certain embodiments, the calcium channel blocker is an amorphoussolid.

In certain embodiments, the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist is a solid.In certain embodiments, the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist is acrystalline solid. In certain embodiments, the histamine H₁-receptoragonist, the histamine H₂-receptor agonist, or the histamine H₃-receptorantagonist is an amorphous solid.

In certain embodiments, the β₂-adrenoreceptor agonist is a solid. Incertain embodiments, the β₂-adrenoreceptor agonist is a crystallinesolid. In certain embodiments, the β₂-adrenoreceptor agonist is anamorphous solid.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the calcium channelblocker in a pharmaceutical composition provided herein is ranging fromabout 1 to about 180, from about 2 to about 100, from about 2 to about50, or from about 2 to about 20. In certain embodiments, the weightratio of (i) the phosphodiesterase inhibitor or adenosine receptorantagonist to (ii) the calcium channel blocker in a pharmaceuticalcomposition provided herein is ranging from about 1 to about 180. Incertain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the calcium channelblocker in a pharmaceutical composition provided herein is ranging fromabout 2 to about 100. In certain embodiments, the weight ratio of (i)the phosphodiesterase inhibitor or adenosine receptor antagonist to (ii)the calcium channel blocker in a pharmaceutical composition providedherein is ranging from about 2 to about 50. In certain embodiments, theweight ratio of (i) the phosphodiesterase inhibitor or adenosinereceptor antagonist to (ii) the calcium channel blocker in apharmaceutical composition provided herein is ranging from about 2 toabout 20. In certain embodiments, the weight ratio of (i) thephosphodiesterase inhibitor or adenosine receptor antagonist to (ii) thecalcium channel blocker in a pharmaceutical composition provided hereinis about 2, about 4, about 6, about 8, about 10, about 12, about 14,about 16, about 18, or about 20.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the histamineH₁-receptor agonist, the histamine H₂-receptor agonist, or the histamineH₃-receptor antagonist in a pharmaceutical composition provided hereinis ranging from about 2 to about 200, from about 4 to about 100, fromabout 5 to about 50, or from about 10 to about 30. In certainembodiments, the weight ratio of (i) the phosphodiesterase inhibitor oradenosine receptor antagonist to (ii) the histamine H₁-receptor agonist,the histamine H₂-receptor agonist, or the histamine H₃-receptorantagonist in a pharmaceutical composition provided herein is rangingfrom about 2 to about 200. In certain embodiments, the weight ratio of(i) the phosphodiesterase inhibitor or adenosine receptor antagonist to(ii) the histamine H₁-receptor agonist, the histamine H₂-receptoragonist, or the histamine H₃-receptor antagonist in a pharmaceuticalcomposition provided herein is ranging from about 4 to about 100. Incertain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the histamineH₁-receptor agonist, the histamine H₂-receptor agonist, or the histamineH₃-receptor antagonist in a pharmaceutical composition provided hereinis ranging from about 5 to about 50. In certain embodiments, the weightratio of (i) the phosphodiesterase inhibitor or adenosine receptorantagonist to (ii) the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist in apharmaceutical composition provided herein is ranging from about 10 toabout 30. In certain embodiments, the weight ratio of (i) thephosphodiesterase inhibitor or adenosine receptor antagonist to (ii) thehistamine H₁-receptor agonist, the histamine H₂-receptor agonist, or thehistamine H₃-receptor antagonist in a pharmaceutical compositionprovided herein is about 10, about 12, about 14, about 16, about 18,about 20, about 22, about 24, about 26, about 28, or about 30.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the β2-adrenoreceptoragonist in a pharmaceutical composition provided herein is ranging fromabout 1 to about 1,000, from about 10 to about 500, from about 20 toabout 400, or from about 40 to about 300. In certain embodiments, theweight ratio of (i) the phosphodiesterase inhibitor or adenosinereceptor antagonist to (ii) the β₂-adrenoreceptor agonist in apharmaceutical composition provided herein is ranging from about 1 toabout 1,000. In certain embodiments, the weight ratio of (i) thephosphodiesterase inhibitor or adenosine receptor antagonist to (ii) theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is ranging from about 10 to about 500. In certain embodiments,the weight ratio of (i) the phosphodiesterase inhibitor or adenosinereceptor antagonist to (ii) the β₂-adrenoreceptor agonist in apharmaceutical composition provided herein is ranging from about 20 toabout 400. In certain embodiments, the weight ratio of (i) thephosphodiesterase inhibitor or adenosine receptor antagonist to (ii) theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is ranging from about 40 to about 300. In certain embodiments,the weight ratio of (i) the phosphodiesterase inhibitor or adenosinereceptor antagonist to (ii) the β₂-adrenoreceptor agonist in apharmaceutical composition provided herein is about 40, about 60, about80, about 100, about 120, about 140, about 160, about 180, about 200,about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist in apharmaceutical composition provided herein is ranging from about 1 toabout 50, from about 1 to about 40, from about 1 to about 20, or fromabout 1 to about 10. In certain embodiments, the weight ratio of (i) thecalcium channel blocker to (ii) the histamine H₁-receptor agonist, thehistamine H₂-receptor agonist, or the histamine H₃-receptor antagonistin a pharmaceutical composition provided herein is ranging from about 1to about 50. In certain embodiments, the weight ratio of (i) the calciumchannel blocker to (ii) the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist in apharmaceutical composition provided herein is ranging from about 1 toabout 40. In certain embodiments, the weight ratio of (i) the calciumchannel blocker to (ii) the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist in apharmaceutical composition provided herein is ranging from about 1 toabout 20. In certain embodiments, the weight ratio of (i) the calciumchannel blocker to (ii) the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist in apharmaceutical composition provided herein is ranging from about 1 toabout 10. In certain embodiments, the weight ratio of (i) the calciumchannel blocker to (ii) the histamine H₁-receptor agonist, the histamineH₂-receptor agonist, or the histamine H₃-receptor antagonist in apharmaceutical composition provided herein is about 1, about 1.5, about2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about9, about 9.5, or about 10. In certain embodiments, the weight ratio of(i) the calcium channel blocker to (ii) the histamine H₁-receptoragonist, the histamine H₂-receptor agonist, or the histamine H₃-receptorantagonist in a pharmaceutical composition provided herein is about 2,about 2.2, about 2.4, about 2.6, about 2.8, about 3, about 3.2, about3.4, about 3.6, about 3.8, or about 4.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) the β₂-adrenoreceptor agonist in a pharmaceuticalcomposition provided herein is ranging from about 1 to about 100, fromabout 5 to about 50, or from about 5 to about 30. In certainembodiments, the weight ratio of (i) the calcium channel blocker to (ii)the β₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is ranging from about 1 to about 100. In certain embodiments, theweight ratio of (i) the calcium channel blocker to (ii) theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is ranging from about 5 to about 50. In certain embodiments, theweight ratio of (i) the calcium channel blocker to (ii) theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is ranging from about 5 to about 30. In certain embodiments, theweight ratio of (i) the calcium channel blocker to (ii) theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is about 5, about 6, about 7, about 8, about 9, about 10, about11, about 12, about 13, about 14, about 15, about 16, about 17, about18, about 19, about 20, about 21, about 22, about 23, about 24, about25, about 26, about 27, about 28, about 29, or about 30.

In certain embodiments, the weight ratio of (i) the histamineH₁-receptor agonist, the histamine H₂-receptor agonist, or the histamineH₃-receptor antagonist to (ii) the β₂-adrenoreceptor agonist in apharmaceutical composition provided herein is ranging from about 1 toabout 100, from about 1 to about 50, from about 1 to about 30, or fromabout 1 to about 20. In certain embodiments, the weight ratio of (i) thehistamine H₁-receptor agonist, the histamine H₂-receptor agonist, or thehistamine H₃-receptor antagonist to (ii) the β₂-adrenoreceptor agonistin a pharmaceutical composition provided herein is ranging from about 1to about 100. In certain embodiments, the weight ratio of (i) thehistamine H₁-receptor agonist, the histamine H₂-receptor agonist, or thehistamine H₃-receptor antagonist to (ii) the β₂-adrenoreceptor agonistin a pharmaceutical composition provided herein is ranging from about 1to about 50. In certain embodiments, the weight ratio of (i) thehistamine H₁-receptor agonist, the histamine H₂-receptor agonist, or thehistamine H₃-receptor antagonist to (ii) the β₂-adrenoreceptor agonistin a pharmaceutical composition provided herein is ranging from about 1to about 30. In certain embodiments, the weight ratio of (i) thehistamine H₁-receptor agonist, the histamine H₂-receptor agonist, or thehistamine H₃-receptor antagonist to (ii) the β₂-adrenoreceptor agonistin a pharmaceutical composition provided herein is ranging from about 1to about 20. In certain embodiments, the weight ratio of (i) thehistamine H₁-receptor agonist, the histamine H₂-receptor agonist, or thehistamine H₃-receptor antagonist to (ii) the β₂-adrenoreceptor agonistin a pharmaceutical composition provided herein is about 1, about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 11, about 12, about 13, about 14, about 15, about 16, about 17,about 18, about 19, or about 20.

In certain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 1 to about 1,200, from about1 to about 1,000, from about 1 to about 800, from about 1 to about 600,from about 2 to about 300, or from about 10 to about 200 mg. In certainembodiments, a pharmaceutical composition provided herein comprises aphosphodiesterase inhibitor or an adenosine receptor antagonist in theamount ranging from about 1 to about 1,200 mg. In certain embodiments, apharmaceutical composition provided herein comprises a phosphodiesteraseinhibitor or an adenosine receptor antagonist in the amount ranging fromabout 1 to about 1,000 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a phosphodiesterase inhibitor oran adenosine receptor antagonist in the amount ranging from about 1 toabout 800 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises a phosphodiesterase inhibitor or an adenosinereceptor antagonist in the amount ranging from about 1 to about 600 mg.In certain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 2 to about 300 mg. Incertain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 10 to about 200 mg. Incertain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount of about 20, about 30, about 40, about 50,about 60, about 70, about 80, about 90, about 100, about 110, about 120,about 130, about 140, about 150, about 160, about 170, about 180, about190, or about 200 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises a calcium channel blocker in the amount ranging from about 0.1to about 200, from about 0.1 to about 100, from about 0.2 to about 80,from about 1 to about 50, or from about 1 to about 30. In certainembodiments, a pharmaceutical composition provided herein comprises acalcium channel blocker in the amount ranging from about 0.1 to about200 mg. In certain embodiments, a pharmaceutical composition providedherein comprises a calcium channel blocker in the amount ranging fromabout 0.1 to about 100 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a calcium channel blocker in theamount ranging from about 0.2 to about 80 mg. In certain embodiments, apharmaceutical composition provided herein comprises a calcium channelblocker in the amount ranging from about 1 to about 50 mg. In certainembodiments, a pharmaceutical composition provided herein comprises acalcium channel blocker in the amount ranging from about 1 to about 30mg. In certain embodiments, a pharmaceutical composition provided hereincomprises a calcium channel blocker in the amount of about 2, about 4,about 6, about 8, about 10, about 12, about 14, about 16, about 18,about 20, about 22, about 24, about 26, about 28, or about 30 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist in the amount rangingfrom about 0.1 to about 200, from about 0.1 to about 100, from about 0.1to about 60, from about 0.2 to about 50, from about 0.5 to about 40, orfrom about 1 to about 30 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist inthe amount ranging from about 0.1 to about 200 mg. In certainembodiments, a pharmaceutical composition provided herein comprises ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist in the amount ranging from about 0.1 toabout 100 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist in the amountranging from about 0.1 to about 60 mg. In certain embodiments, apharmaceutical composition provided herein comprises a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist in the amount ranging from about 0.2 to about 50mg. In certain embodiments, a pharmaceutical composition provided hereincomprises a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist in the amount rangingfrom about 0.5 to about 40 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist inthe amount ranging from about 1 to about 3 mg. In certain embodiments, apharmaceutical composition provided herein comprises a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist in the amount of about 1, about 5, about 10,about 15, about 20, about 25, or about 30 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises a β₂-adrenoreceptor agonist in the amount ranging from about0.01 to about 60, from about 0.01 to about 40, from about 0.05 to about30, from about 0.05 to about 20, or from about 0.1 to about 10, or fromabout 0.1 to about 5 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a β₂-adrenoreceptor agonist in theamount ranging from about 0.01 to about 60 mg. In certain embodiments, apharmaceutical composition provided herein comprises a β₂-adrenoreceptoragonist in the amount ranging from about 0.01 to about 40 mg. In certainembodiments, a pharmaceutical composition provided herein comprises aβ₂-adrenoreceptor agonist in the amount ranging from about 0.05 to about30 mg. In certain embodiments, a pharmaceutical composition providedherein comprises a β₂-adrenoreceptor agonist in the amount ranging fromabout 0.05 to about 20 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a β₂-adrenoreceptor agonist in theamount ranging from about 0.1 to about 10 mg. In certain embodiments, apharmaceutical composition provided herein comprises a β₂-adrenoreceptoragonist in the amount ranging from about 0.1 to about 5 mg. In certainembodiments, a pharmaceutical composition provided herein comprises aβ₂-adrenoreceptor agonist in the amount of about 0.1, about 0.5, about1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about4.5, or about 5 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 1 to about 90, from about 2to about 80, from about 5 to 60, or from about 5 to about 35% by weight.In certain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 1 to about 90% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 2 to about 80% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 5 to about 60% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 5 to about 35% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount of about 5, about 10, about 15, about 20, about25, about 30, about 35, about 40, about 45, about 50, about 55, or about60% by weight.

In certain embodiments, a pharmaceutical composition provided hereincomprises a calcium channel blocker in the amount ranging from about 0.1to about 30, from about 0.5 to about 20, or from about 1 to about 10% byweight. In certain embodiments, a pharmaceutical composition providedherein comprises a calcium channel blocker in the amount ranging fromabout 0.1 to about 30% by weight. In certain embodiments, apharmaceutical composition provided herein comprises a calcium channelblocker in the amount ranging from about 0.5 to about 20% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises a calcium channel blocker in the amount ranging from about 1to about 10% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a calcium channel blocker in theamount of about 1, about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, or about 10% by weight.

In certain embodiments, a pharmaceutical composition provided hereincomprises a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist in the amount rangingfrom about 0.02 to about 30, from about 0.05 to about 20, from about 0.1to about 15, or from about 0.2 to about 10% by weight. In certainembodiments, a pharmaceutical composition provided herein comprises ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist in the amount ranging from about 0.02to about 30% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist inthe amount ranging from about 0.05 to about 20% by weight. In certainembodiments, a pharmaceutical composition provided herein comprises ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist in the amount ranging from 0.1 to about15% by weight. In certain embodiments, a pharmaceutical compositionprovided herein comprises a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist in the amountranging from 0.2 to about 10% by weight. In certain embodiments, apharmaceutical composition provided herein comprises a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist in the amount of about 0.2, about 0.5, about 1.0,about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5,about 8.0, about 8.5, about 9.0, about 9.5, or about 10% by weight.

In certain embodiments, a pharmaceutical composition provided hereincomprises a β₂-adrenoreceptor agonist in the amount ranging from about0.005 to about 10, from about 0.01 to about 8, from about 0.02 to about6, from about 0.05 to about 5% by weight. In certain embodiments, apharmaceutical composition provided herein comprises a β₂-adrenoreceptoragonist in the amount ranging from about 0.005 to about 10% by weight.In certain embodiments, a pharmaceutical composition provided hereincomprises a β₂-adrenoreceptor agonist in the amount ranging from about0.01 to about 8% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a β₂-adrenoreceptor agonist in theamount ranging from about 0.02 to about 6% by weight. In certainembodiments, a pharmaceutical composition provided herein comprises aβ₂-adrenoreceptor agonist in the amount ranging from about 0.05 to about5% by weight. In certain embodiments, a pharmaceutical compositionprovided herein comprises a β₂-adrenoreceptor agonist in the amount ofabout 0.05, about 0.1, about 1, about 1.5, about 2.0, about 2.5, about3.0, about 3.5, about 4.0, about 4.5, or about 5% by weight.

Phosphodiesterase Inhibitors or Adenosine Receptor Antagonists

In some embodiments, a pharmaceutical composition provided hereincomprises an API that is a phosphodiesterase (PDE) inhibitor and/or anadenosine receptor antagonist. PDE inhibitors and adenosine receptorantagonists are primarily used in the treatment of chronic obstructivepulmonary disease (COPD) and asthma. One secondary therapeutical effectof this API is that it increases heart rate and cardiac output. Themolecular mechanism of action of this API as a phosphodiesteraseinhibitor and/or and enosine receptor is (i) inhibiting aphosphodiesterase competitively and nonselectively, which increaseintracellular cyclic adenosine monophosphate (cAMP), activates proteinkinase A (PKA), inhibits tumor necrosis factor (TNF)-alpha, inhibitsleukotriene synthesis, and reduces inflammation and innate immunity; and(ii) antagonizing nonselectively an adenosine receptor, antagonizing A₁,A₂, and A₃ receptors almost equally, which explains many of its cardiaceffects. By inhibiting a phosphodiesterase, the hydrolysis of cycliccAMP is reduced, thus promoting endogenous epinephrine and controllingnorepinephrine release. An adenosine receptor antagonist can antagonizeadenosine and prevent the excessive release of adenosine, consequentlyincreasing cAMP in myocardial cells resulting in an increase in heartrate (HR) and cardiac output. When taken in a combination of two or moreAPIs provided herein, the undesired side effects of this API, whichincludes an increase in myocardial contractility, myocardial metabolism,and oxygen consumption, can be minimized or even eliminated by thecounteracting reduction of oxygen consumption and myocardial metabolisminduced by another API such as a calcium channel blocker disclosedherein. Meanwhile, the desired effects can be enhanced that include, butare not limited to, increased heart rate and cardiac output using acombination of two or more APIs provided herein.

The present disclosure discloses a surprising finding that, when used aspart of a combination of two or more APIs provided herein, a PDEinhibitor and/or adenosine receptor antagonist is useful in thetreatment of bradycardia while avoiding or minimizing certain associatedundesired side effects.

In certain embodiments, the phosphodiesterase (PDE) inhibitor is axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the PDE inhibitor is a methylxanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof. In certain embodiments, the PDE inhibitor is caffeine,doxophylline, dyphylline, oxtriphylline, paraxanthine, pentoxifylline,theobromine, theophylline, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the PDE inhibitor is aminophylline, caffeine,doxophylline, dyphylline, oxtriphylline, paraxanthine, pentoxifylline,theobromine, or theophylline. In certain embodiments, the PDE inhibitoris aminophylline, caffeine, doxophylline, dyphylline, oxtriphylline,pentoxifylline, or theophylline. In certain embodiments, the PDEinhibitor is aminophylline. In certain embodiments, the PDE inhibitor iscaffeine. In certain embodiments, the PDE inhibitor is doxophylline. Incertain embodiments, the PDE inhibitor is dyphylline. In certainembodiments, the PDE inhibitor is oxtriphylline. In certain embodiments,the PDE inhibitor is pentoxifylline. In certain embodiments, the PDEinhibitor is theophylline.

In certain embodiments, the PDE inhibitor is a nonselective PDEinhibitor. In certain embodiments, the PDE inhibitor is a competitivenonselective PDE inhibitor. In certain embodiments, the nonselective PDEinhibitor is caffeine, paraxanthine, pentoxifylline, theobromine,theophylline, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.

In certain embodiments, the PDE inhibitor is a PDE1 inhibitor. Incertain embodiments, the PDE inhibitor is a PDE1 selective inhibitor. Incertain embodiments, the PDE1 inhibitor is vinpocetine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In certain embodiments, the PDE inhibitor is a PDE2 inhibitor. Incertain embodiments, the PDE inhibitor is a PDE2 selective inhibitor. Incertain embodiments, the PDE2 inhibitor is EHNA(erythro-9-(2-hydroxy-3-nonyl)adenine), BAY 60-7550(2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one), oxindole, PDP(9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In certain embodiments, the PDE inhibitor is a PDE3 inhibitor. Incertain embodiments, the PDE inhibitor is a PDE3 selective inhibitor. Incertain embodiments, the PDE3 inhibitor is anagrelide, cilostazol,enoximone, inamrinone, milrinone, pimobendan, or an isotopic variantthereof or a pharmaceutically acceptable salt, hydrate, or solvatethereof.

In certain embodiments, the PDE inhibitor is a PDE4 inhibitor. Incertain embodiments, the PDE inhibitor is a PDE4 selective inhibitor. Incertain embodiments, the PDE4 inhibitor is apremilast, drotaverine,ibudilast, luteolin, mesembrine, piclamilast, roflumilast, rolipram, oran isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In certain embodiments, the PDE inhibitor is a PDE5 inhibitor. Incertain embodiments, the PDE inhibitor is a PDE5 selective inhibitor. Incertain embodiments, the PDE5 inhibitor is avanafil, dipyridamole,icariin, sildenafil, tadalafil, udenafil, vardenafil, or an isotopicvariant thereof or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the PDE5 inhibitor is4-methylpiperazine, pyrazolo pyrimidin-7-1, or an isotopic variantthereof or a pharmaceutically acceptable salt, hydrate, or solvatethereof.

In certain embodiments, the PDE inhibitor is a PDE7 inhibitor. Incertain embodiments, the PDE inhibitor is a PDE7 selective inhibitor. Incertain embodiments, the PDE7 inhibitor is quinazoline or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In certain embodiments, the PDE inhibitor is a PDE10 inhibitor. Incertain embodiments, the PDE inhibitor is a PDE10 selective inhibitor.In certain embodiments, the PDE10 inhibitor is papaverine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In certain embodiments, the PDE inhibitor is adibendan, amipizone,anagrelide, apremilast, arofylline, atizoram, avanafil, befuraline,bemarinone, bemoradan, benafentrine, bucladesine, buflomedil,buquineran, CC-1088, carbazeran, catramilast, cilomilast, cilostazol,crisaborole (AN2728), dipyridamole, drotaverin, enoximone, etamiphyllin,ibudilast, inamrinone, luteolin, mesembrenone, metescufylline,midaxifylline, milrinone, motapizone, papaverine, parogrelil, pelrinone,pentifylline, pentoxifylline, perbufylline, piclamilast, pimefylline,pimobendan, piroximone, prinoxodan, proxyphylline, pumafentrine,roflumilast, rolipram, sildenafil, tadalafil, theophylline, udenafil,vardenafil, vinpocetine, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof.

In certain embodiments, the PDE inhibitor is AN2728, adibendan,aminophylline, aminophylline dihydrate, amipizone, arofylline, atizoram,befuraline, bemarinone hydrochloride, bemoradan, benafentrine,bucladesine, buflomedil, buquineran, CC-1088, carbazeran, catramilast,cilomilast, cilostamide, cilostazol, cipamfylline, daxalipram,denbufylline, dimabefylline, diniprofylline, dipyridamole, doxofylline,drotaverine, dyphylline, enoximone, etamiphyllin, etofylline,filaminast, flufylline, fluprofylline, furafylline, imazodan, imazodanhydrochloride, inamrinone, inamrinone lactate, isbufylline, lirimilast,lisofylline, lomifylline, medorinone, metescufylline, midaxifylline,milrinone, milrinone lactate, motapizone, nanterinone, nestifylline,nitraquazone, oglemilast, oglemilast sodium, olprinone, oxagrelate,oxtriphylline, papaverine, papaverine hydrochloride, papaverine sulfate,parogrelil, pelrinone hydrochloride, pentifylline, pentoxifylline,perbufylline, piclamilast, pimefylline, pimobendan, piroximone,prinoxodan, proxyphylline, pumafentrine, quazinone, quazodine,revamilast, revizinone, roflumilast, rolipram, ronomilast, saterinone,senazodan, siguazodan, tetomilast, theophylline, tofimilast, trapidil,vesnarinone, or zardaverine.

In certain embodiments, the PDE inhibitor is aminotadalafil, avanafil,beminafil, dasantafil, gisadenafil, gisadenafil besylate, mirodenafil,sildenafil, sildenafil citrate, tadalafil, udenafil, vardenafil,vardenafil dihydrochloride, vardenafil hydrochloride trihydrate, orzaprinast.

In certain embodiments, the adenosine receptor antagonist is a xanthinecompound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the adenosine receptor antagonist is a methylxanthine compound or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the adenosinereceptor antagonist is caffeine, paraxanthine, pentoxifylline,theobromine, theophylline, or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the adenosine receptor antagonist is aminophylline,caffeine, doxophylline, dyphylline, oxtriphylline, paraxanthine,pentoxifylline, theobromine, or theophylline. In certain embodiments,the adenosine receptor antagonist is aminophylline. In certainembodiments, the adenosine receptor antagonist is theophylline.

In certain embodiments, the adenosine receptor antagonist is anonselective adenosine receptor antagonist. In certain embodiments, theadenosine receptor antagonist is an A₁ antagonist. In certainembodiments, the adenosine receptor antagonist is an A₂ antagonist. Incertain embodiments, the adenosine receptor antagonist is an A₃antagonist. In certain embodiments, the adenosine receptor antagonist isan antagonist of A₁, A₂, and A₃ receptors.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)one or more compounds, wherein each compound is independently a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof and (ii) acalcium channel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) a calcium channelblocker. In another embodiment, the pharmaceutical composition comprises(i) a xanthine compound or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a histamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist. In yet another embodiment, thepharmaceutical composition comprises (i) a xanthine compound or anisotopic variant thereof or a pharmaceutically acceptable salt, hydrate,or solvate thereof and (ii) a β₂-adrenoreceptor agonist.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; and (ii) two compounds, wherein each compound is independentlya calcium channel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a calcium channelblocker; and (iii) a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist. In anotherembodiment, the pharmaceutical composition comprises (i) a xanthinecompound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a calcium channelblocker; and (iii) a β₂-adrenoreceptor agonist. In yet anotherembodiment, the pharmaceutical composition comprises (i) a xanthinecompound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist; and (iii) a β₂-adrenoreceptor agonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; and (ii) three compounds, wherein each compound isindependently a calcium channel blocker, a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, a histamine H₃-receptorantagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a calcium channelblocker; (iii) a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist; and (iv) aβ₂-adrenoreceptor agonist.

In certain embodiments, the xanthine compound is a methylxanthine. Incertain embodiments, the xanthine compound is caffeine, doxophylline,dyphylline, oxtriphylline, paraxanthine, pentoxifylline, theobromine,theophylline, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the xanthine compound is aminophylline, caffeine, doxophylline,dyphylline, oxtriphylline, paraxanthine, pentoxifylline, theobromine, ortheophylline. In certain embodiments, the xanthine compound isaminophylline. In certain embodiments, the xanthine compound istheophylline.

In certain embodiments, the xanthine compound or an isotopic variantthereof, or a pharmaceutically acceptable salt, hydrate, or solvatethereof is a solid. In certain embodiments, the xanthine compound or anisotopic variant thereof, or a pharmaceutically acceptable salt,hydrate, or solvate thereof is a crystalline solid. In certainembodiments, the xanthine compound or an isotopic variant thereof, or apharmaceutically acceptable salt, hydrate, or solvate thereof is anamorphous solid.

In certain embodiments, the weight ratio of the xanthine compound to thecalcium channel blocker in a pharmaceutical composition provided hereinis ranging from about 1 to about 180, from about 2 to about 100, fromabout 2 to about 50, or from about 2 to about 20. In certainembodiments, the weight ratio of the xanthine compound to the calciumchannel blocker in a pharmaceutical composition provided herein isranging from about 1 to about 180. In certain embodiments, the weightratio of the xanthine compound to the calcium channel blocker in apharmaceutical composition provided herein is ranging from about 2 toabout 100. In certain embodiments, the weight ratio of the xanthinecompound to the calcium channel blocker in a pharmaceutical compositionprovided herein is ranging from about 2 to about 50. In certainembodiments, the weight ratio of the xanthine compound to the calciumchannel blocker in a pharmaceutical composition provided herein isranging from about 2 to about 20. In certain embodiments, the weightratio of the xanthine compound to the calcium channel blocker in apharmaceutical composition provided herein is about 2, about 4, about 6,about 8, about 10, about 12, about 14, about 16, about 18, or about 20.

In certain embodiments, the weight ratio of (i) the xanthine compound to(ii) the histamine H₁-receptor agonist, histamine H₂-receptor agonist,or histamine H₃-receptor antagonist in a pharmaceutical compositionprovided herein is ranging from about 2 to about 200, from about 4 toabout 100, from about 5 to about 50, or from about 10 to about 30. Incertain embodiments, the weight ratio of (i) the xanthine compound to(ii) the histamine H₁-receptor agonist, histamine H₂-receptor agonist,or histamine H₃-receptor antagonist in a pharmaceutical compositionprovided herein is about 10, about 12, about 14, about 16, about 17,about 18, about 19, about 20, about 21, about 22, about 23, about 24,about 25, about 26, about 27, about 28, about 29, or about 30.

In certain embodiments, the weight ratio of the xanthine compound to theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is ranging from about 1 to about 1,000, from about 10 to about500, from about 20 to about 400, or from about 40 to about 300. Incertain embodiments, the weight ratio of the xanthine compound to theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is about 40, about 60, about 80, about 100, about 120, about 140,about 160, about 180, about 200, about 220, about 240, about 260, about280, or about 300.

In certain embodiments, a pharmaceutical composition provided hereincomprises a xanthine compound in the amount ranging from about 1 toabout 1,200, from about 1 to about 1,000, from about 1 to about 800,from about 1 to about 600, from about 2 to about 300, or from about 20to about 200 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises a xanthine compound in the amount ranging fromabout 1 to about 1,200 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a xanthine compound in the amountranging from about 1 to about 1,000 mg. In certain embodiments, apharmaceutical composition provided herein comprises a xanthine compoundin the amount ranging from about 1 to about 800 mg. In certainembodiments, a pharmaceutical composition provided herein comprises axanthine compound in the amount ranging from about 1 to about 600 mg. Incertain embodiments, a pharmaceutical composition provided hereincomprises a xanthine compound in the amount ranging from about 2 toabout 300 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises a xanthine compound in the amount ranging fromabout 10 to about 200 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a xanthine compound in the amountof about 10, about 20, about 30, about 40, about 50, about 60, about 70,about 80, about 90, about 100, about 110, about 120, about 130, about140, about 150, about 160, about 170, about 180, about 190, or about 200mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises a xanthine compound in the amount ranging from about 1 toabout 90, from about 2 to about 80, from 5 to about 60, or from about 5to about 35% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a xanthine compound in the amountranging from about 1 to about 90% by weight. In certain embodiments, apharmaceutical composition provided herein comprises a xanthine compoundin the amount ranging from about 2 to about 80% by weight. In certainembodiments, a pharmaceutical composition provided herein comprises axanthine compound in the amount ranging from about 5 to about 60% byweight. In certain embodiments, a pharmaceutical composition providedherein comprises a xanthine compound in the amount ranging from about 5to about 35% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a xanthine compound in the amountof about 5, about 10, about 15, about 20, about 25, about 30, or about35% by weight.

Calcium Channel Blockers

In some embodiments, a pharmaceutical composition provided hereincomprises an API that is a calcium channel blocker. Calcium channelblockers are commonly used in the treatment of high blood pressure. Byblocking calcium channels, these APIs relax coronary artery systems andprevent coronary artery spasms (thus dilating the main coronary arteriesand coronary arterioles, both in normal and ischemic region), andfurther reduce oxygen utilization, thereby reducing arterial pressure bydilating peripheral arterioles and reducing the total peripheralresistance against which the heart works. The undesired side effectsincluding, but not limited to, inhibition of myocardial contractilityand reduction in myocardial metabolism, are minimized or eliminated bycounteracting effects induced by another API in the combination such asan API that is a PDE inhibitor or an adenosine receptor antagonist.Meanwhile, desired effects can be enhanced that include, but are notlimited to, increased heart rate and cardiac output using a combinationof two or more APIs provided herein.

The present disclosure discloses a surprisingly finding that, when usedas part of a combination provided herein, calcium channel blockers areuseful in the treatment of bradycardia while avoiding or minimizingcertain associated undesired side effects.

In certain embodiments, the calcium channel blocker is amlodipine,aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine,clevidipine, diltiazem, efonidipine, felodipine, fendiline, gabapentin,gallopamil, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, pranidipine, pregabalin, verapamil, ziconotide, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is bepridil, flunarizine, fluspirilene, mibefradil, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In certain embodiments, the calcium channel blocker is a dihydropyridineor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is amlodipine, aranidipine, azelnidipine, barnidipine,benidipine, cilnidipine, clevidipine, efonidipine, felodipine,isradipine, lacidipine, lercanidipine, manidipine, nicardipine,nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine,pranidipine, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.

In certain embodiments, the calcium channel blocker is amlodipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is aranidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is azelnidipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is barnidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is benidipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is bepridil or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is cilnidipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is clevidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is diltiazem or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is efonidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is felodipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is fendiline or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is flunarizine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is fluspirilene or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is gallopamil or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is isradipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is lacidipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is lercanidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is manidipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is mibefradil or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is nicardipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is nifedipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is nilvadipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is nimodipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is nisoldipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is nitrendipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is pranidipine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the calcium channelblocker is verapamil or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the calcium channel blocker is ziconotide or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)one or more compounds, wherein each compound is independently a PDEinhibitor, an adenosine receptor antagonist, a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, a histamine H₃-receptorantagonist, or a β₂-adrenoreceptor agonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a PDE inhibitor, an adenosine receptor antagonist, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) a PDE inhibitoror an adenosine receptor antagonist. In another embodiment, thepharmaceutical composition comprises (i) a dihydropyridine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist. Inyet another embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) aβ₂-adrenoreceptor agonist.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; and (ii) two compounds, wherein each compound is independentlya PDE inhibitor, an adenosine receptor antagonist, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a PDE inhibitor or anadenosine receptor antagonist; and (iii) a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, or a histamine H₃-receptorantagonist. In another embodiment, the pharmaceutical compositioncomprises (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) aPDE inhibitor or an adenosine receptor antagonist; and (iii) aβ₂-adrenoreceptor agonist. In yet another embodiment, the pharmaceuticalcomposition comprises (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist; and (iii) aβ₂-adrenoreceptor agonist.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; and (ii) three compounds, wherein each compound isindependently a PDE inhibitor, an adenosine receptor antagonist, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, ahistamine H₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a PDE inhibitor or anadenosine receptor antagonist; (iii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist;and (iv) a β₂-adrenoreceptor agonist.

In certain embodiments, the dihydropyridine is amlodipine, aranidipine,azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine,cronidipine, darodipine, dexniguldipine, efonidipine, elgodipine,elnadipine, felodipine, flordipine, furnidipine, iganidine, isradipine,lacidipine, lemildipine, lercanidipine, levamlodipine, levniguldipine,manidipine, nicardipine, nifedipine, niguldipine, niludipine,nivadipine, nimodipine, nisoldipine, nitrendipine, olradipine,oxodipine, palonidipine, pranidipine, ryodipine, sagandipine,sornidipine, teludipine, tiamdipine, trombodipine, vatanidipine, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In certain embodiments, the dihydropyridine is amlodipine, aranidipine,azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine,efonidipine, felodipine, isradipine, lacidipine, lercanidipine,levamlodipine, manidipine, nicardipine, nifedipine, nivadipine,nimodipine, nisoldipine, nitrendipine, pranidipine, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In certain embodiments, the dihydropyridine is amlodipine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the dihydropyridine isaranidipine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the dihydropyridine is azelnidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the dihydropyridine is barnidipine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the dihydropyridine isbenidipine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the dihydropyridine is cilnidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the dihydropyridine is clevidipine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the dihydropyridine isefonidipine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the dihydropyridine is felodipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the dihydropyridine is isradipine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the dihydropyridine islacidipine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the dihydropyridine is lercanidipine or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the dihydropyridine is levamlodipine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the dihydropyridine ismanidipine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the dihydropyridine is nicardipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the dihydropyridine is nifedipine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the dihydropyridine isnivadipine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the dihydropyridine is nimodipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the dihydropyridine is nisoldipine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the dihydropyridine isnitrendipine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof. In certain embodiments,the dihydropyridine is pranidipine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof.

In certain embodiments, the dihydropyridine or an isotopic variantthereof, or a pharmaceutically acceptable salt, hydrate, or solvatethereof is a solid. In certain embodiments, the dihydropyridine or anisotopic variant thereof, or a pharmaceutically acceptable salt,hydrate, or solvate thereof is a crystalline solid. In certainembodiments, the dihydropyridine or an isotopic variant thereof, or apharmaceutically acceptable salt, hydrate, or solvate thereof is anamorphous solid.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the dihydropyridinein a pharmaceutical composition provided herein is ranging from about 1to about 180, from about 2 to about 100, or from about 2 to about 20. Incertain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the dihydropyridinein a pharmaceutical composition provided herein is about 2, about 3,about 4, about 5, about 6, about 7, about 8, about 9, about 10, about11, about 12, about 13, about 14, about 15, about 16, about 17, about18, about 19, or about 20.

In certain embodiments, the weight ratio of (i) the dihydropyridine to(ii) the histamine H₁-receptor agonist, histamine H₂-receptor agonist,or histamine H₃-receptor antagonist in a pharmaceutical compositionprovided herein is ranging from about 0.1 to about 50, from about 1 toabout 40, from about 1 to about 20, or from about 1 to about 10. Incertain embodiments, the weight ratio of (i) the dihydropyridine to (ii)the histamine H₁-receptor agonist, histamine H₂-receptor agonist, orhistamine H₃-receptor antagonist in a pharmaceutical compositionprovided herein is about 1, about 1.5, about 2, about 2.5, about 3,about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5,about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.In certain embodiments, the weight ratio of (i) the dihydropyridine to(ii) the histamine H₁-receptor agonist, histamine H₂-receptor agonist,or histamine H₃-receptor antagonist in a pharmaceutical compositionprovided herein is about 2, about 2.2, about 2.4, about 2.6, about 2.8,about 3, about 3.2, about 3.4, about 3.6, about 3.8, or about 4.

In certain embodiments, the weight ratio of the dihydropyridine to theβ₂-adrenoreceptor agonist in a pharmaceutical composition providedherein is ranging from about 1 to about 100, from about 5 to about 50,or from about 5 to about 30. In certain embodiments, the weight ratio ofthe dihydropyridine to the β₂-adrenoreceptor agonist in a pharmaceuticalcomposition provided herein is about 5, about 6, about 7, about 8, about9, about 10, about 11, about 12, about 13, about 14, about 15, about 16,about 17, about 18, about 19, about 20, about 21, about 22, about 23,about 24, about 25, about 26, about 27, about 28, about 29, or about 30.

In certain embodiments, a pharmaceutical composition provided hereincomprises a dihydropyridine in the amount ranging from about 0.1 toabout 200, from about 0.1 to about 100, from about 0.2 to about 80, fromabout 1 to about 50, or from about 1 to about 30 mg. In certainembodiments, a pharmaceutical composition provided herein comprises adihydropyridine in the amount ranging from about 0.1 to about 200 mg. Incertain embodiments, a pharmaceutical composition provided hereincomprises a dihydropyridine in the amount ranging from about 0.1 toabout 100 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises a dihydropyridine in the amount ranging fromabout 0.2 to about 80 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a dihydropyridine in the amountranging from about 1 to about 50 mg. In certain embodiments, apharmaceutical composition provided herein comprises a dihydropyridinein the amount ranging from about 1 to about 30 mg. In certainembodiments, a pharmaceutical composition provided herein comprises adihydropyridine in the amount of about 1, about 2, about 4, about 6,about 8, about 10, about 12, about 14, about 16, about 18, about 20,about 22, about 24, about 26, about 28, or about 30 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises a dihydropyridine in the amount ranging from about 0.1 toabout 30, from about 0.5 to about 20, or from about 1 to about 10% byweight. In certain embodiments, a pharmaceutical composition providedherein comprises a dihydropyridine in the amount ranging from about 0.1to about 30% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises a dihydropyridine in the amountranging from about 0.5 to about 20% by weight. In certain embodiments, apharmaceutical composition provided herein comprises a dihydropyridinein the amount ranging from about 1 to about 10% by weight. In certainembodiments, a pharmaceutical composition provided herein comprises adihydropyridine in the amount of about 1, about 2, about 3, about 4,about 5, about 6, about 7, about 8, about 9, or about 10% by weight.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (iii) optionally twoor more compounds, wherein each compound is independently a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a dihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a histamine H₁-receptor agonist, a histamine H₂-receptor agonist, ahistamine H₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a dihydropyridine oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.In another embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a dihydropyridine oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) a β₂-adrenoreceptor agonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)two compounds, wherein each compound is independently a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a dihydropyridine oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (iii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist;and (iv) a β₂-adrenoreceptor agonist.

In certain embodiments, the weight ratio of the xanthine compound to thedihydropyridine in a pharmaceutical composition provided herein isranging from about 1 to about 180, from about 2 to about 100, from about2 to about 50, or from about 2 to about 20. In certain embodiments, theweight ratio of the xanthine compound to the dihydropyridine in apharmaceutical composition provided herein is ranging from about 1 toabout 180. In certain embodiments, the weight ratio of the xanthinecompound to the dihydropyridine in a pharmaceutical composition providedherein is ranging from about 2 to about 100. In certain embodiments, theweight ratio of the xanthine compound to the dihydropyridine in apharmaceutical composition provided herein is ranging from about 2 toabout 50. In certain embodiments, the weight ratio of the xanthinecompound to the dihydropyridine in a pharmaceutical composition providedherein is ranging from about 2 to about 20. In certain embodiments, theweight ratio of the xanthine compound to the dihydropyridine in apharmaceutical composition provided herein is about 2, about 4, about 6,about 8, about 10, about 12, about 14, about 16, about 18, or about 20.

Histamine H₁-Receptor Agonists, Histamine H₂-Receptor Agonists, orHistamine H₃-Receptor Antagonists

In some embodiments, a pharmaceutical composition provided hereincomprises an API that is a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, and/or a histamine H₃ receptor antagonist. Similarto PDE inhibitors, adenosine receptor antagonists, and calcium channelblockers, when used in a therapeutically effective amount, a variety ofundesired side effects are associated with a histamine H₁-receptoragonist, H₂-receptor agonist, or histamine H₃ receptor antagonist forits currently approved indication(s). A histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist isknown to be useful in the treatment of vertigo. Without wishing to bebound by theory, there are two potential modes of action for a histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist. First, some histamine H₃ receptor antagonistscan have a stimulating effect on H₁ receptors, giving rise to localvasodilation and permeability. Second, antagonistic effects on H₃receptors can cause an increase in the levels of histamine,acetylcholine, norepinephrine, serotonin, and γ-aminobutyric acid (GABA)released from nerve endings, causing vasodilatory effect, includingreduced blood pressure. These undesired side effects can be minimized oreliminated by counteracting effects induced by another API such as aβ₂-adrenoreceptor agonist (e.g., albuterol or levalbuterol) providedherein. Meanwhile, desired effects can be enhanced that include, but arenot limited to, increased dilation of peripheral small arteries andvenules, resulting in an increase in HR and cardiac output using acombination of two or more APIs provided herein.

The present disclosure discloses a surprising finding that, when used aspart of a combination of two or more APIs provided herein, the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist is useful in the treatment of bradycardia whileavoiding certain associated undesired side effects.

In certain embodiments, the histamine H₁-receptor agonist is histamine,HTMT (histamine trifluoromethyl toluidide), 2-pyridylethylamine,2-thiazolylethylamine, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist is betahistine,betazole, impentamine, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist is betazole oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist is impentamine or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof.

In certain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist is4-methylhistamine, dimaprit, impromidine, or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof.

In certain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist is A-349,821,ABT-239, betahistine, burimamide, ciproxifan, clobenpropit, conessine,failproxifan, impentamine, indophenpropit, irdabisant, pitolisant,theioperamide, VUF-5681 (4-[3-(1H-imidazol-4-yl)propyl]piperidine), oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist is betahistine or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist is betahistinehydrochloride.

In certain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist is a metaboliteof betahistine. In certain embodiments, the metabolite is2-(2-aminoethyl)pyridine, 2-(2-hydroxyethyl)pyridine, or pyridylaceticacid. In certain embodiments, the histamine H₁-receptor agonist,histamine H₂-receptor agonist, or histamine H₃-receptor antagonist is2-(2-aminoethyl)pyridine, 2-(2-hydroxyethyl)pyridine, or pyridylaceticacid.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) one or more compounds, wherein each compoundis independently a PDE inhibitor, an adenosine receptor antagonist, acalcium channel blocker, or a β₂-adrenergic receptor agonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) a PDE inhibitor, an adenosine receptorantagonist, a calcium channel blocker, or a β₂-adrenergic receptoragonist.

In one embodiment, the pharmaceutical composition comprises (i)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) a PDE inhibitor or an adenosine receptor antagonist. In anotherembodiment, the pharmaceutical composition comprises (i) betahistine, ora metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a calcium channel blocker. In yet another embodiment, the pharmaceuticalcomposition comprises (i) betahistine, or a metabolite thereof, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) a β₂-adrenergic receptor agonist.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) betahistine, or a metabolite thereof, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) two compounds, wherein eachcompound is independently a PDE inhibitor, an adenosine receptorantagonist, a calcium channel blocker, or a β₂-adrenergic receptoragonist.

In one embodiment, the pharmaceutical composition comprises (i)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) aPDE inhibitor or adenosine receptor antagonist; and (iii) a calciumchannel blocker. In another embodiment, the pharmaceutical compositioncomprises (i) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) a PDE inhibitor or adenosine receptor antagonist;and (iii) a β₂-adrenergic receptor agonist. In yet another embodiment,the pharmaceutical composition comprises (i) betahistine, or ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) acalcium channel blocker; and (iii) a β₂-adrenergic receptor agonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) betahistine, or a metabolite thereof, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) three compounds, wherein eachcompound is independently a PDE inhibitor, an adenosine receptorantagonist, a calcium channel blocker, or a β₂-adrenergic receptoragonist.

In one embodiment, the pharmaceutical composition comprises (i)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) aPDE inhibitor or an adenosine receptor antagonist; (iii) a calciumchannel blocker; and (iv) a β₂-adrenergic receptor agonist.

In certain embodiments, the betahistine, or a metabolite thereof, or anisotopic variant thereof, or a pharmaceutically acceptable salt,hydrate, or solvate thereof is a solid. In certain embodiments, thebetahistine, or a metabolite thereof, or an isotopic variant thereof, ora pharmaceutically acceptable salt, hydrate, or solvate thereof is acrystalline solid. In certain embodiments, the betahistine, or ametabolite thereof, or an isotopic variant thereof, or apharmaceutically acceptable salt, hydrate, or solvate thereof is anamorphous solid.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) betahistine or ametabolite thereof in a pharmaceutical composition provided herein isranging from about 2 to about 200, from about 4 to about 100, from about5 to about 50, or from about 10 to about 30. In certain embodiments, theweight ratio of (i) the phosphodiesterase inhibitor or adenosinereceptor antagonist to (ii) betahistine or a metabolite thereof in apharmaceutical composition provided herein is about 10, about 12, about14, about 16, about 17, about 18, about 19, about 20, about 21, about22, about 23, about 24, about 25, about 26, about 27, about 28, about29, or about 30.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) betahistine or a metabolite thereof in a pharmaceuticalcomposition provided herein is ranging from about 1 to about 50, fromabout 1 to about 40, from about 1 to about 20, or from about 1 to about10. In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) betahistine or a metabolite thereof in a pharmaceuticalcomposition provided herein is about 1, about 1.5, about 2, about 2.5,about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6,about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5,or about 10. In certain embodiments, the weight ratio of (i) the calciumchannel blocker to (ii) betahistine or a metabolite thereof in apharmaceutical composition provided herein is about 2, about 2.2, about2.4, about 2.6, about 2.8, about 3, about 3.2, about 3.4, about 3.6,about 3.8, or about 4.

In certain embodiments, the weight ratio of (i) betahistine or ametabolite thereof to (ii) the β₂-adrenoreceptor agonist in apharmaceutical composition provided herein is ranging from about 1 toabout 100, from about 1 to about 50, from about 1 to about 30, or fromabout 1 to about 20. In certain embodiments, the weight ratio of (i)betahistine or a metabolite thereof to (ii) the β₂-adrenoreceptoragonist in a pharmaceutical composition provided herein is about 1,about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9,about 10, about 11, about 12, about 13, about 14, about 15, about 16,about 17, about 18, about 19, or about 20.

In certain embodiments, a pharmaceutical composition provided hereincomprises betahistine or a metabolite thereof in the amount ranging fromabout 0.1 to about 200, from about 0.1 to about 100, from about 0.1 toabout 60, from about 0.2 to about 50, from about 0.5 to about 40, orfrom about 1 to about 30 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises betahistine or a metabolitethereof in the amount ranging from about 0.1 to about 200 mg. In certainembodiments, a pharmaceutical composition provided herein comprisesbetahistine or a metabolite thereof in the amount ranging from about 0.1to about 100 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises betahistine or a metabolite thereof in theamount ranging from about 0.1 to about 60 mg. In certain embodiments, apharmaceutical composition provided herein comprises betahistine or ametabolite thereof in the amount ranging from about 0.2 to about 50 mg.In certain embodiments, a pharmaceutical composition provided hereincomprises betahistine or a metabolite thereof in the amount ranging fromabout 0.5 to about 40 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises betahistine or a metabolitethereof in the amount ranging from about 1 to about 30 mg. In certainembodiments, a pharmaceutical composition provided herein comprisesbetahistine or a metabolite thereof in the amount of about 1, about 2,about 4, about 6, about 8, about 10, about 12, about 14, about 16, about18, about 20, about 22, about 24, about 26, about 28, or about 30 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises betahistine or a metabolite thereof in the amount ranging fromabout 0.02 to about 30, from about 0.05 to about 20, from about 0.1 toabout 15, or from about 0.2 to about 10% by weight. In certainembodiments, a pharmaceutical composition provided herein comprisesbetahistine or a metabolite thereof in the amount ranging from about0.02 to about 30% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises betahistine or a metabolitethereof in the amount ranging from about 0.05 to about 20% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises betahistine or a metabolite thereof in the amount ranging from0.1 to about 15% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises betahistine or a metabolitethereof in the amount ranging from 0.2 to about 10% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises betahistine or a metabolite thereof in the amount of about0.2, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0,about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5,or about 10% by weight.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(iii) optionally one or more compounds, wherein each compound isindependently a calcium channel blocker or a β₂-adrenergic receptoragonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a calcium channel blocker or a β₂-adrenergicreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) betahistine, or ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a calcium channel blocker. In another embodiment, the pharmaceuticalcomposition comprises (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a β₂-adrenergic receptor agonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) two compounds, wherein each compound isindependently a calcium channel blocker or a β₂-adrenergic receptoragonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) betahistine, or ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii) acalcium channel blocker; and (iv) a β₂-adrenergic receptor agonist.

In certain embodiments, the weight ratio of the xanthine compound tobetahistine or a metabolite thereof in a pharmaceutical compositionprovided herein is ranging from about 2 to about 200, from about 4 toabout 100, from about 5 to about 50, or from about 10 to about 30. Incertain embodiments, the weight ratio of the xanthine compound tobetahistine or a metabolite thereof in a pharmaceutical compositionprovided herein is about 10, about 12, about 14, about 16, about 17,about 18, about 19, about 20, about 21, about 22, about 23, about 24,about 25, about 26, about 27, about 28, about 29, or about 30.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(iii) optionally one or more compounds, wherein each compound isindependently a phosphodiesterase inhibitor, an adenosine receptorantagonist, or a β2-adrenoreceptor agonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a phosphodiesterase inhibitor, an adenosinereceptor antagonist, and/or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) betahistine, or ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a phosphodiesterase inhibitor or an adenosine receptor antagonist. Inanother embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) betahistine, or ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a β₂-adrenoreceptor agonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) two compounds, wherein each compound isindependently a phosphodiesterase inhibitor, an adenosine receptorantagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) betahistine, or ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii) aphosphodiesterase inhibitor or an adenosine receptor antagonist; and(iv) a β₂-adrenoreceptor agonist.

In certain embodiments, the weight ratio of the dihydropyridine tobetahistine or a metabolite thereof in a pharmaceutical compositionprovided herein is ranging from about 1 to about 50, from about 1 toabout 40, from about 1 to about 20, or from about 1 to about 10. Incertain embodiments, the weight ratio of the dihydropyridine tobetahistine or a metabolite thereof in a pharmaceutical compositionprovided herein is about 1, about 1.5, about 2, about 2.5, about 3,about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5,about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.In certain embodiments, the weight ratio of the dihydropyridine tobetahistine or a metabolite thereof in a pharmaceutical compositionprovided herein is about 2, about 2.2, about 2.4, about 2.6, about 2.8,about 3.0, about 3.2, about 3.4, about 3.6, about 3.8, or about 4.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (iii) betahistine, or ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iv)optionally a β₂-adrenoreceptor agonist.

β₂-Adrenoreceptor Agonists

In some embodiments, a pharmaceutical composition provided hereincomprises an API that is a β₂-adrenoreceptor agonist. Similar to PDEinhibitors, adenosine receptor antagonists, calcium channel blockers,histamine H₁-receptor agonists; histamine H₂-receptor agonists orhistamine H₃-receptor antagonists, when used in a therapeuticallyeffective amount, a variety of undesirable side effects are associatedwith β₂-adrenoreceptor agonists for its currently approvedindication(s). β₂-Adrenoreceptor agonists are known to be useful in thetreatment of asthma. One secondary therapeutical effect of this API isthat it can increase heart rate and cardiac output. Albuterol is aracemic mixture of R-albuterol and S-albuterol. The molecular mechanismof action of this API includes, but is not limited to, that (i) the(R)-enantiomer (levalbuterol) is responsible for the pharmacologicactivity and (ii) the (5)-enantiomer blocks metabolic pathways. The APIis known as a short-acting β₂-adrenergic receptor agonist originallyused for the relief of bronchospasm. Additionally, this API can alsostimulate the heart B₁ receptor. The heart myocardium also has the B₂receptor. By excitement of B₂ and B₁ receptors, the heart rate can beincreased. Side effects of this API include the increase of bloodpressure. These undesired side effect can be minimized or eliminated bycounteracting effects induced by another API such as a histamine H₁-and/or H₂-receptor agonist and/or a histamine H₃-receptor antagonist(e.g., betahistine) provided herein. Meanwhile, desired effects can beenhanced that include, but are not limited to, increased heart rate andcardiac output using a combination of two or more APIs provided herein.

The present disclosure discloses a surprising finding that, when used asa part of a combination of two or more APIs provided herein, aβ₂-adrenoreceptor agonist is useful in the treatment of bradycardiawhile avoiding or minimizing certain associated undesired side effects.

In one embodiment, the β₂-adrenergic receptor agonist is a short-actingβ₂ agonist. In another embodiment, the β₂-adrenergic receptor agonist isa long-acting β₂ agonist. In yet another embodiment, the β₂-adrenergicreceptor agonist is an ultra-long-acting β₂ agonist.

In certain embodiments, the β₂-adrenergic receptor agonist is albuterol,bambuterol, bitolterol, clenbuterol, fenoterol, formoterol, indacaterol,isoprenaline, levalbuterol, metaproterenol, olodaterol, pirbuterol,procaterol, ritodrine, salbutamol, terbutaline, vilanterol, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is albuterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is bambuterol oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is bitolterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is clenbuterolor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is fenoterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is formoterol oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is indacaterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is isoprenalineor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is levalbuterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist ismetaproterenol or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.

In certain embodiments, the β₂-adrenergic receptor agonist is olodaterolor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is pirbuterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is procaterol oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is ritodrine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is salbutamol oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is terbutaline or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is vilanterol oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In certain embodiments, the β₂-adrenergic receptor agonist isarfomoterol, bupherine, dopexamine, epinephrine, isoestarine,isoproterenol, levosalbutamol, orciprenaline, salmeterol, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof. In certain embodiments, the β₂-adrenergic receptoragonist is arfomoterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is bupherine oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is dopexamine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is epinephrineor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is isoestarine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is isoproterenolor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is levosalbutamol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof. Incertain embodiments, the β₂-adrenergic receptor agonist is orciprenalineor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate or solvate thereof. In certain embodiments, the β₂-adrenergicreceptor agonist is salmeterol or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) one or morecompounds, wherein each compound is independently a PDE inhibitor, anadenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) a compound thatis a PDE inhibitor, an adenosine receptor antagonist, a calcium channelblocker, a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist.

In one embodiment, the pharmaceutical composition comprises (i)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) a PDE inhibitor or an adenosinereceptor antagonist. In another embodiment, the pharmaceuticalcomposition comprises (i) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a calcium channel blocker. In yet another embodiment, the pharmaceuticalcomposition comprises (i) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a histamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)two compounds, wherein each compound is independently a PDE inhibitor,an adenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In one embodiment, the pharmaceutical composition comprises (i)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) a PDE inhibitor or adenosine receptorantagonist; and (iii) a calcium channel blocker. In another embodiment,the pharmaceutical composition comprises (i) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) a PDE inhibitor or adenosine receptor antagonist;and (iii) a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist. In yet anotherembodiment, the pharmaceutical composition comprises (i) albuterol, oran enantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) a calcium channel blocker; and (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)three compounds, wherein each compound is independently a PDE inhibitor,an adenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In one embodiment, the pharmaceutical composition comprises (i)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) a PDE inhibitor or an adenosinereceptor antagonist; (iii) a calcium channel blocker; and (iv) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In certain embodiments, the albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; is asolid. In certain embodiments, the albuterol, or an enantiomer, amixture of enantiomers; or levalbuterol; or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof; is acrystalline solid. In certain embodiments, the albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; is an amorphous solid.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) albuterol orlevalbuterol in a pharmaceutical composition provided herein is rangingfrom about 1 to about 1,000, from about 10 to about 500, from about 20to about 400, or from about 40 to about 300. In certain embodiments, theweight ratio of (i) the phosphodiesterase inhibitor or adenosinereceptor antagonist to (ii) albuterol or levalbuterol in apharmaceutical composition provided herein is about 40, about 60, about70, about 80, about 90, about 100, about 110, about 120, about 130,about 140, about 160, about 180, about 200, about 220, about 240, about260, about 280, or about 300.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) albuterol in a pharmaceutical composition providedherein is ranging from about 1 to about 100, from about 5 to about 50,or from about 5 to about 30. In certain embodiments, the weight ratio of(i) the calcium channel blocker to (ii) albuterol or levalbuterol in apharmaceutical composition provided herein is about 5, about 6, about 8,about 10, about 12, about 14, about 16, about 18, about 20, about 22,about 24, about 26, about 28, or about 30.

In certain embodiments, the weight ratio of (i) the histamineH₁-receptor agonist, the histamine H₂-receptor agonist, or the histamineH₃-receptor antagonist to (ii) albuterol or levalbuterol in apharmaceutical composition provided herein is ranging from about 1 toabout 100, from about 1 to about 50, from about 1 to about 30, or fromabout 1 to about 20. In certain embodiments, the weight ratio of (i) thehistamine H₁-receptor agonist, the histamine H₂-receptor agonist, or thehistamine H₃-receptor antagonist to (ii) albuterol or levalbuterol in apharmaceutical composition provided herein is about 1, about 2, about 3,about 4, about 5, about 6, about 7, about 8, about 9, about 10, about11, about 12, about 13, about 14, about 15, about 16, about 17, about18, about 19, or about 20.

In certain embodiments, a pharmaceutical composition provided hereincomprises albuterol or levalbuterol (micronized or non-micronized) inthe amount ranging from about 0.01 to about 60, from about 0.01 to about40, from about 0.05 to about 30, from about 0.05 to about 20, from about0.1 to about 10, or from about 0.1 to about 5 mg. In certainembodiments, a pharmaceutical composition provided herein comprisesalbuterol or levalbuterol in the amount ranging from about 0.01 to about60 mg. In certain embodiments, a pharmaceutical composition providedherein comprises albuterol or levalbuterol in the amount ranging fromabout 0.05 to about 30 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises albuterol or levalbuterol in theamount ranging from about 0.05 to about 20 mg. In certain embodiments, apharmaceutical composition provided herein comprises albuterol orlevalbuterol in the amount ranging from about 0.1 to about 10 mg. Incertain embodiments, a pharmaceutical composition provided hereincomprises albuterol or levalbuterol in the amount ranging from about 0.1to about 5 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises albuterol or levalbuterol in the amount ofabout 0.1, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about3.0, about 3.5, about 4.0, about 4.5, or about 5 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises albuterol or levalbuterol in the amount ranging from about0.005 to about 10, from about 0.01 to about 8, from about 0.02 to about6, from about 0.05 to about 5% by weight. In certain embodiments, apharmaceutical composition provided herein comprises albuterol orlevalbuterol in the amount ranging from about 0.005 to about 10% byweight. In certain embodiments, a pharmaceutical composition providedherein comprises albuterol or levalbuterol in the amount ranging fromabout 0.01 to about 8% by weight. In certain embodiments, apharmaceutical composition provided herein comprises albuterol orlevalbuterol in the amount ranging from about 0.02 to about 6% byweight. In certain embodiments, a pharmaceutical composition providedherein comprises albuterol or levalbuterol in the amount ranging fromabout 0.05 to about 5% by weight. In certain embodiments, apharmaceutical composition provided herein comprises albuterol orlevalbuterol in the amount of about 0.1, about 0.5, about 1.0, about1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5,or about 5% by weight.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) optionally one or more compounds,wherein each compound is independently a calcium channel blocker, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof and (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (iii) a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a calcium channel blocker. In anotherembodiment, the pharmaceutical composition comprises (i) a xanthinecompound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (iii) two compounds,wherein each compound is independently a calcium channel blocker, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In one embodiment, the pharmaceutical composition comprises (i) axanthine compound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (iii) a calcium channel blocker; and (iv) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In certain embodiments, the weight ratio of (i) the xanthine compound to(ii) albuterol or levalbuterol in a pharmaceutical composition providedherein is ranging from about 1 to about 1,000, from about 10 to about500, from about 20 to about 400, or from about 40 to about 300. Incertain embodiments, the weight ratio of (i) the xanthine compound to(ii) albuterol or levalbuterol in a pharmaceutical composition providedherein is about 40, about 60, about 80, about 100, about 120, about 140,about 160, about 180, about 200, about 220, about 240, about 260, about280, or about 300.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) optionally one or more compounds,wherein each compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (iii) a phosphodiesteraseinhibitor, an adenosine receptor antagonist; and (iv) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In one embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a phosphodiesterase inhibitor or an adenosinereceptor antagonist. In another embodiment, the pharmaceuticalcomposition comprises (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (iii) two compounds,wherein each compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.

In one embodiment, the pharmaceutical composition comprises (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (iii) a phosphodiesterase inhibitor or an adenosinereceptor antagonist; and (iv) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.

In certain embodiments, the weight ratio of (i) the dihydropyridine to(ii) albuterol or levalbuterol in a pharmaceutical composition providedherein is ranging from about 1 to about 100, from about 5 to about 50,or from about 5 to about 30. In certain embodiments, the weight ratio of(i) the dihydropyridine to (ii) albuterol or levalbuterol in apharmaceutical composition provided herein is about 5, about 10, about12, about 14, about 16, about 18, about 20, about 22, about 24, about26, about 28, or about 30.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)optionally one or more compounds, wherein each compound is independentlya phosphodiesterase inhibitor, an adenosine receptor antagonist, or acalcium channel blocker.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) betahistine, or a metabolite thereof, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) albuterol, or an enantiomer, a mixtureof enantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a phosphodiesterase inhibitor, an adenosine receptor antagonist, or acalcium channel blocker.

In one embodiment, the pharmaceutical composition comprises (i)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) a phosphodiesterase inhibitor oran adenosine receptor antagonist. In another embodiment, thepharmaceutical composition comprises (i) betahistine, or a metabolitethereof, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a calcium channel blocker.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) betahistine, or a metabolite thereof, or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) albuterol, or an enantiomer, a mixtureof enantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)two compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, or acalcium channel blocker.

In one embodiment, the pharmaceutical composition comprises (i)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (iii) a phosphodiesterase inhibitor or anadenosine receptor antagonist; and (iv) a calcium channel blocker.

In certain embodiments, the weight ratio of (i) betahistine or ametabolite thereof to (ii) albuterol or levalbuterol in a pharmaceuticalcomposition provided herein is ranging from about 1 to about 100, fromabout 1 to about 50, from about 1 to about 30, or from about 1 to about20. In certain embodiments, the weight ratio of (i) betahistine or ametabolite thereof to (ii) albuterol or levalbuterol in a pharmaceuticalcomposition provided herein is about 1, about 2, about 3, about 4, about5, about 6, about 7, about 8, about 9, about 10, about 11, about 12,about 13, about 14, about 15, about 16, about 17, about 18, about 19, orabout 20.

In one embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (iii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iv) optionally a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.

In another embodiment, provided herein is a pharmaceutical compositioncomprising (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (iii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iv) optionally a calcium channelblocker.

In yet another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a dihydropyridine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) betahistine, or a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (iii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iv)optionally a PDE inhibitor or an adenosine receptor antagonist.

In still another embodiment, provided herein is a pharmaceuticalcomposition comprising (i) a xanthine compound or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof (ii) a dihydropyridine or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii)betahistine, or a metabolite thereof, or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(iv) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.

In one embodiment, the xanthine compound is aminophylline ortheophylline. In another embodiment, the dihydropyridine is nifedipine.

In one embodiment, a pharmaceutical composition provided hereincomprises aminophylline or theophylline. In another embodiment, apharmaceutical composition provided herein comprises nifedipine. In yetanother embodiment, a pharmaceutical composition provided hereincomprises betahistine or betahistine hydrochloride. In still anotherembodiment, a pharmaceutical composition provided herein comprisesalbuterol, albuterol hydrochloride, levalbuterol, or levalbuterolhydrochloride.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) aminophylline or theophylline and (ii) nifedipine.

In another embodiment, a pharmaceutical composition provided hereincomprises (i) aminophylline or theophylline and (ii) betahistine orbetahistine hydrochloride.

In yet another embodiment, a pharmaceutical composition provided hereincomprises (i) aminophylline or theophylline and (ii) albuterol,albuterol hydrochloride, levalbuterol, or levalbuterol hydrochloride.

In yet another embodiment, a pharmaceutical composition provided hereincomprises (i) nifedipine and (ii) betahistine or betahistinehydrochloride.

In yet another embodiment, a pharmaceutical composition provided hereincomprises (i) nifedipine and (ii) albuterol, albuterol hydrochloride,levalbuterol, or levalbuterol hydrochloride.

In still another embodiment, a pharmaceutical composition providedherein comprises (i) betahistine or betahistine hydrochloride; and (ii)albuterol, albuterol hydrochloride, levalbuterol, or levalbuterolhydrochloride.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) aminophylline or theophylline; (ii) nifedipine; and (iii)betahistine or betahistine hydrochloride.

In another embodiment, a pharmaceutical composition provided hereincomprises (i) aminophylline or theophylline; (ii) nifedipine; and (iii)albuterol, albuterol hydrochloride, levalbuterol, or levalbuterolhydrochloride.

In yet another embodiment, a pharmaceutical composition provided hereincomprises (i) nifedipine; (ii) betahistine or betahistine hydrochloride;and (iii) albuterol, albuterol hydrochloride, levalbuterol, orlevalbuterol hydrochloride.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) aminophylline or theophylline; (ii) nifedipine; (iii)betahistine or betahistine hydrochloride; and (iv) albuterol, albuterolhydrochloride, levalbuterol, or levalbuterol hydrochloride.

In certain embodiments, aminophylline is a solid. In certainembodiments, aminophylline is a crystalline solid. In certainembodiments, aminophylline is an amorphous solid. In certainembodiments, theophylline is a solid. In certain embodiments,theophylline is a crystalline solid. In certain embodiments,theophylline is an amorphous solid.

In certain embodiments, nifedipine is a solid. In certain embodiments,nifedipine is a crystalline solid. In certain embodiments, nifedipine isan amorphous solid.

In certain embodiments, the weight ratio of theophylline to nifedipinein a pharmaceutical composition provided herein is ranging from about 1to about 180, from about 2 to about 100, from about 2 to about 50, orfrom about 2 to about 20. In certain embodiments, the weight ratio oftheophylline to nifedipine in a pharmaceutical composition providedherein is ranging from about 1 to about 180. In certain embodiments, theweight ratio of theophylline to nifedipine in a pharmaceuticalcomposition provided herein is ranging from about 2 to about 100. Incertain embodiments, the weight ratio of theophylline to nifedipine in apharmaceutical composition provided herein is ranging from about 2 toabout 50. In certain embodiments, the weight ratio of theophylline tonifedipine in a pharmaceutical composition provided herein is rangingfrom about 2 to about 20. In certain embodiments, the weight ratio oftheophylline to nifedipine in a pharmaceutical composition providedherein is about 2, about 4, about 6, about 8, about 10, about 12, about14, about 16, about 18, or about 20.

In certain embodiments, the weight ratio of theophylline to betahistinein a pharmaceutical composition provided herein is ranging from about 2to about 200, from about 4 to about 100, from about 5 to about 50, orfrom about 10 to about 30. In certain embodiments, the weight ratio oftheophylline to betahistine in a pharmaceutical composition providedherein is about 10, about 12, about 14, about 16, about 18, about 20,about 22, about 24, about 26, about 28, or about 30.

In certain embodiments, the weight ratio of theophylline to albuterol orlevalbuterol in a pharmaceutical composition provided herein is rangingfrom about 1 to about 1,000, from about 10 to about 500, from about 20to about 200, or from about 40 to about 300. In certain embodiments, theweight ratio of theophylline to albuterol or levalbuterol in apharmaceutical composition provided herein is about 40, about 60, about80, about 100, about 120, about 140, about 160, about 180, about 200,about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, the weight ratio of nifedipine to betahistine ina pharmaceutical composition provided herein is ranging from about 1 toabout 50, from about 1 to about 40, from about 1 to about 20, or fromabout 1 to about 10. In certain embodiments, the weight ratio ofnifedipine to betahistine in a pharmaceutical composition providedherein is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5,about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7,about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, the weight ratio of betahistine to albuterol orlevalbuterol in a method provided herein is ranging from about 1 toabout 100, from about 5 to about 50, from about 5 to about 30, or fromabout 1 to about 20. In certain embodiments, the weight ratio ofbetahistine to albuterol or levalbuterol in a method provided herein isabout 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8,about 9, about 10, about 11, about 12, about 13, about 14, about 15,about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, a pharmaceutical composition provided hereincomprises theophylline in the amount ranging from about 1 to about1,200, from about 1 to about 1,000, from about 1 to about 800, fromabout 1 to about 600, from about 2 to about 300, or from about 10 toabout 200 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises theophylline in the amount ranging from about1 to about 1,200 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 1 to about 1,000 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 1 to about 800 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 1 to about 600 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 2 to about 300 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 10 to about 200 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount ofabout 10, about 20, about 40, about 60, about 80, about 100, about 120,about 140, about 160, about 180, or about 200 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises aminophylline in the amount ranging from about 1 to about1,200, from about 1 to about 1,000, from about 1 to about 800, fromabout 1 to about 600, from about 2 to about 300, or from about 10 toabout 200 mg. In certain embodiments, a pharmaceutical compositionprovided herein comprises theophylline in the amount ranging from about1 to about 1,200 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 1 to about 1,000 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 1 to about 800 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 1 to about 600 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 2 to about 300 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 10 to about 200 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount ofabout 10, about 20, about 40, about 60, about 80, about 100, about 120,about 140, about 160, about 180, or about 200 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises nifedipine (micronized or non-micronized) in the amountranging from about 0.1 to about 200, about 0.1 to about 100, about 0.2to about 80, from about 1 to about 50, from about 1 to about 30, or fromabout 1 to about 20 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount rangingfrom about 0.1 to about 200 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount rangingfrom about 0.1 to about 100 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount rangingfrom about 0.2 to about 80 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount rangingfrom about 1 to about 50 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount rangingfrom about 1 to about 30 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount rangingfrom about 1 to about 20 mg. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount of about1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about9, about 10, about 11, about 12, about 13, about 14, about 15, about 16,about 17, about 18, about 19, or about 20 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises theophylline in the amount ranging from about 1 to about 90,from about 2 to about 80, from about 5 to about 60, or from about 5 toabout 35% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises theophylline in the amount rangingfrom about 1 to about 90% by weight. In certain embodiments, apharmaceutical composition provided herein comprises theophylline in theamount ranging from about 2 to about 80% by weight. In certainembodiments, a pharmaceutical composition provided herein comprisestheophylline in the amount ranging from about 5 to about 60% by weight.In certain embodiments, a pharmaceutical composition provided hereincomprises theophylline in the amount ranging from about 5 to about 35%by weight. In certain embodiments, a pharmaceutical composition providedherein comprises theophylline in the amount of about 5, about 10, about20, about 30, or about 35% by weight.

In certain embodiments, a pharmaceutical composition provided hereincomprises nifedipine in the amount ranging from about 0.1 to about 30,from about 0.5 to about 20, or from about 1 to about 10% by weight. Incertain embodiments, a pharmaceutical composition provided hereincomprises nifedipine in the amount ranging from about 0.1 to about 30%by weight. In certain embodiments, a pharmaceutical composition providedherein comprises nifedipine in the amount ranging from about 0.5 toabout 20% by weight. In certain embodiments, a pharmaceuticalcomposition provided herein comprises nifedipine in the amount rangingfrom about 1 to about 10% by weight. In certain embodiments, apharmaceutical composition provided herein comprises nifedipine in theamount of about 1, about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, or about 10% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 10 to about 200 mg and (ii)a calcium channel blocker in the amount ranging from about 1 to about 20mg. In another embodiment, a pharmaceutical composition provided hereincomprises (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 5 to about 35% by weight and(ii) a calcium channel blocker in the amount ranging from about 1 toabout 10% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist in the amount rangingfrom about 1 to about 30 mg and (ii) a β₂-adrenoreceptor agonist in theamount ranging from about 0.1 to about 5 mg. In another embodiment, apharmaceutical composition provided herein comprises (i) a histamine H₁-and/or H₂-receptor agonist, and/or a histamine H₃-receptor antagonist inthe amount ranging from about 0.2 to about 10% by weight and (ii) aβ₂-adrenoreceptor agonist in the amount ranging from about 0.05 to about5% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist, in an embodiment, theophylline, aminophylline, or ahydrochloride thereof, in the amount ranging from about 5 to about 90%or from about 10 to about 35% by weight; (ii) a calcium channel blocker,in an embodiment, nifedipine, in the amount ranging from about 1 toabout 20% or from about 1 to about 5% by weight; (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist, in an embodiment, betahistine, or a metabolitethereof, or a hydrochloride thereof, in the amount ranging from about0.1 to about 20% or from about 1 to about 5% by weight; (iv) aβ₂-adrenoreceptor agonist, in an embodiment, albuterol, levalbuterol, ora hydrochloride thereof, in the amount ranging from about 0.05 to about5% or from about 0.1 to about 0.5% by weight; and (v) a pharmaceuticallyacceptable excipient, in an embodiment, a diluent, a binder, adisintegrate, a glidant, a lubricant, a preservative, or a mixturethereof.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof in theamount ranging from about 10 to about 200 mg; (ii) a dihydropyridine oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof in the amount ranging from about 1 to about20 mg; (iii) betahistine, or a metabolite thereof, or an isotopicvariant thereof, or a pharmaceutically acceptable salt thereof in theamount ranging from about 1 to about 20 mg; and (iv) albuterol,levalbuterol, or an isotopic variant thereof, or a pharmaceuticallyacceptable salt thereof in the amount ranging from about 0.1 to about 5mg. In another embodiment, a pharmaceutical composition provided hereincomprises (i) a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof in theamount ranging from about 5 to about 90% by weight; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof in the amount ranging fromabout 1 to about 20% by weight; (iii) betahistine, or a metabolitethereof, or an isotopic variant thereof, or a pharmaceuticallyacceptable salt thereof in the amount ranging from about 0.1 to about20% by weight; and (iv) albuterol, levalbuterol, or an isotopic variantthereof, or a pharmaceutically acceptable salt thereof in the amountranging from about 0.05 to about 5% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) theophylline in the amount ranging from about 10 to about200 mg; (ii) nifedipine in the amount ranging from about 1 to about 20mg; (iii) betahistine or a hydrochloride thereof in the amount rangingfrom about 0.1 to about 20 mg; and (iv) albuterol, levalbuterol, or ahydrochloride thereof in the amount ranging from about 0.1 to about 5mg. In another embodiment, a pharmaceutical composition provided hereincomprises (i) theophylline in the amount ranging from about 5 to about90% by weight; (ii) nifedipine in the amount ranging from about 1 toabout 20% by weight; (iii) betahistine or a hydrochloride thereof in theamount ranging from about 0.1 to about 20% by weight; and (iv)albuterol, levalbuterol or a hydrochloride thereof in the amount rangingfrom about 0.05 to about 5% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) a xanthine compound, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof in theamount ranging from about 10 to about 200 mg; and (ii) a dihydropyridineor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof in the amount ranging from about 1 to about20 mg; In another embodiment, a pharmaceutical composition providedherein comprises (i) a xanthine compound or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof inthe amount ranging from about 5 to about 90% by weight; and (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof in the amount ranging fromabout 1 to about 20% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) a xanthine compound, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof in theamount ranging from about 10 to about 200 mg; (ii) a dihydropyridine oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof in the amount ranging from about 1 to about20 mg; and (iii) betahistine, or a metabolite thereof, or an isotopicvariant thereof, or a pharmaceutically acceptable salt thereof in theamount ranging from about 1 to about 20 mg; In another embodiment, apharmaceutical composition provided herein comprises (i) a xanthinecompound or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof in the amount ranging fromabout 5 to about 90% by weight; (ii) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof in the amount ranging from about 1 to about 20% byweight; and (iii) betahistine, or a metabolite thereof, or an isotopicvariant thereof, or a pharmaceutically acceptable salt thereof in theamount ranging from about 0.1 to about 20% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) theophylline in the amount ranging from about 10 to about200 mg; (ii) nifedipine in the amount ranging from about 1 to about 20mg; (iii) betahistine or a hydrochloride thereof in the amount rangingfrom about 0.1 to about 20 mg; In another embodiment, a pharmaceuticalcomposition provided herein comprises (i) theophylline in the amountranging from about 5 to about 90% by weight; (ii) nifedipine in theamount ranging from about 1 to about 20% by weight; (iii) betahistine ora hydrochloride thereof in the amount ranging from about 0.1 to about20% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) theophylline in the amount ranging from about 10 to about200 mg; (ii) nifedipine in the amount ranging from about 1 to about 20mg; and (iii) albuterol, levalbuterol, or a hydrochloride thereof in theamount ranging from about 0.1 to about 5 mg. In another embodiment, apharmaceutical composition provided herein comprises (i) theophylline inthe amount ranging from about 5 to about 90% by weight; (ii) nifedipinein the amount ranging from about 1 to about 20% by weight; (iii)albuterol, levalbuterol, or a hydrochloride thereof in the amountranging from about 0.05 to about 5% by weight.

In one embodiment, a pharmaceutical composition provided hereincomprises (i) theophylline in the amount ranging from about 10 to about200 mg; (ii) betahistine or a hydrochloride thereof in the amountranging from about 0.1 to about 20 mg; and (iii) albuterol,levalbuterol, or a hydrochloride thereof in the amount ranging fromabout 0.1 to about 5 mg. In another embodiment, a pharmaceuticalcomposition provided herein comprises (i) theophylline thereof in theamount ranging from about 5 to about 90% by weight; (ii) betahistine ora hydrochloride thereof in the amount ranging from about 0.1 to about20% by weight; (iii) albuterol, levalbuterol, or a hydrochloride thereofin the amount ranging from about 0.05 to about 5% by weight.

In certain embodiments, a pharmaceutical composition provided hereincomprises a diluent, a binder, a disintegrate, a glidant, a lubricant,or a preservative, or a mixture thereof. In certain embodiments, apharmaceutical composition provided herein comprises a diluent, abinder, a disintegrate, a glidant, a lubricant, and a preservative.

In certain embodiments, the amount of the diluent in a pharmaceuticalcomposition provided herein is ranging from about 10 to about 60, fromabout 10 to about 50, from about 10 to about 45, or from about 10 toabout 35% by weight. In certain embodiments, the amount of the diluentin a pharmaceutical composition provided herein is about 10, about 12,about 14, about 16, about 18, about 20, about 22, about 24, about 26,about 28, about 30, about 32, about 34, or about 35% by weight.

In certain embodiments, the amount of the binder in a pharmaceuticalcomposition provided herein is ranging from about 10 to about 65, about10 to about 50, about 10 to about 45, or about 10 to about 35% byweight. In certain embodiments, the amount of the binder in apharmaceutical composition provided herein is about 10, about 12, about14, about 16, about 18, about 20, about 22, about 24, about 26, about28, about 30, about 32, about 34, or about 35% by weight.

In certain embodiments, the amount of the disintegrant in apharmaceutical composition provided herein is ranging from about 1 toabout 5%, or from about 1 to about 3% by weight. In certain embodiments,the amount of the disintegrant in a pharmaceutical composition providedherein is about 1, about 1.5, about 2, about 2.5, or about 3% by weight.

In certain embodiments, the amount of the glidant in a pharmaceuticalcomposition provided herein is ranging from about 0.01 to about 0.5,from about 0.02 to about 0.3% by weight. In certain embodiments, theamount of the glidant in a pharmaceutical composition provided herein isabout 0.02, about 0.05, about 0.10, about 0.15, about 0.20, about 0.25,or about 0.3% by weight.

In certain embodiments, the amount of the lubricant in a pharmaceuticalcomposition provided herein is ranging from about 0.05 to about 0.8 orfrom about 0.1 to about 0.5% by weight. In certain embodiments, theamount of the lubricant in a pharmaceutical composition provided hereinis about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35,about 0.4, about 0.45, or about 0.5% by weight.

In certain embodiments, the amount of the preservative in apharmaceutical composition provided herein is ranging from about 0.1 toabout 2 or from about 0.2 to about 1% by weight. In certain embodiments,the amount of the preservative in a pharmaceutical composition providedherein is about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about0.7, about 0.8, about 0.9, or about 1% by weight.

In certain embodiments, a pharmaceutical composition provided hereincomprises a diluent in the amount ranging from about 10 to about 65% byweight; the binder is in the amount ranging from about 10 to about 65%by weight; the disintegrant is in the amount ranging from about 1 toabout 5% by weight; the glidant is in the amount ranging from about 0.01to about 0.5% by weight; the lubricant is in the amount ranging fromabout 0.05 to about 0.8% by weight; and/or the preservative is in theamount ranging from about 0.1 to about 2% by weight.

In certain embodiments, a pharmaceutical composition provided hereinfurther comprises a diluent in the amount ranging from about 50 to about450 mg, a binder in the amount ranging from about 50 to about 450 mg, adisintegrant in the amount ranging from about 1 to about 25 mg, aglidant in the amount ranging from about 0.1 to about 2 mg, a lubricantin the amount ranging from about 0.2 to about 3 mg, and a preservativein the amount ranging from about 0.5 to about 5 mg.

In certain embodiments, a pharmaceutical composition provided hereincomprises a diluent, a binder, a disintegrate, a glidant, a lubricant,or a preservative, or a mixture thereof. In certain embodiments, apharmaceutical composition provided herein comprises a diluent, abinder, a disintegrate, a glidant, a lubricant, and a preservative.

In certain embodiments, the diluent in a pharmaceutical compositionprovided herein is microcrystalline cellulose, lactose, or corn starch.In certain embodiments, the diluent in a pharmaceutical compositionprovided herein is microcrystalline cellulose. In certain embodiments,the binder in a pharmaceutical composition provided herein is mannitol.In certain embodiments, the disintegrant in a pharmaceutical compositionprovided herein is sodium starch glycolate or crospovidone. In certainembodiments, the disintegrant in a pharmaceutical composition providedherein is sodium starch glycolate. In certain embodiments, the glidantin a pharmaceutical composition provided herein is colloidal silicondioxide. In certain embodiments, the lubricant in a pharmaceuticalcomposition provided herein is magnesium stearate. In certainembodiments, the preservative in a pharmaceutical composition providedherein is citric acid.

In certain embodiments, in a pharmaceutical composition provided herein,the diluent is microcrystalline cellulose; the binder is mannitol; thedisintegrant is sodium starch glycolate; the glidant is colloidalsilicon dioxide; the lubricant is magnesium stearate; and thepreservative is citric acid.

Without being bound by any theory, a solution provided herein tobradycardia treatment is to take advantages of the side effects (e.g.,increasing heart rate and/or cardiac output) of certain therapeuticagents at their prescribed doses for approved indication(s). Forexample, one of the known side effects of theophylline is a rapidheartbeat, along with an increase in oxygen consumption. One of theknown side effects of nifedipine is also a rapid heartbeat, along with areduction in oxygen consumption. Thus, theophylline and nifedipine arepaired together to achieve the desired heart rate increase without asubstantial effect on oxygen consumption. One of the known side effectsof betahistine is a rapid heartbeat, along with a reduction in bloodpressure. One of the known side effects of levalbuterol is a rapidheartbeat, along with an increase in blood pressure. Thus, betahistineand levalbuterol are paired together to achieve the desired heart rateincrease without a substantial effect on blood pressure.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Where acompound provided herein contains an alkenyl group, the compound mayexist as one or mixture of geometric cis/trans (or Z/E) isomers. Wherestructural isomers are interconvertible, the compound may exist as asingle tautomer or a mixture of tautomers. This can take the form ofproton tautomerism in the compound that contains, for example, an imino,keto, or oxime group; or so-called valence tautomerism in the compoundthat contain an aromatic moiety.

A compound provided herein can be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof ordinary skill in the art will recognize that administration of acompound in its (R) form is equivalent, for compounds that undergoepimerization in vivo, to administration of the compound in its (5)form. Conventional techniques for the preparation/isolation ofindividual enantiomers include synthesis from a suitable optically pureprecursor, asymmetric synthesis from achiral starting materials, orresolution of an enantiomeric mixture, for example, chiralchromatography, recrystallization, resolution, diastereomeric saltformation, or derivatization into diastereomeric adducts followed byseparation.

When a compound provided herein contains an acidic or basic moiety, itcan also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2011).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine,trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of a compound, for example, of Formula I and isreadily convertible into the parent compound in vivo. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent compound. They may, for instance, be bioavailable byoral administration whereas the parent compound is not. The prodrug mayalso have enhanced solubility in pharmaceutical compositions over theparent compound. A prodrug may be converted into the parent drug byvarious mechanisms, including enzymatic processes and metabolichydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294;Morozowich et al. in “Design of Biopharmaceutical Properties throughProdrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

The pharmaceutical compositions provided herein can be formulated invarious dosage forms for oral, parenteral, and topical administration.The pharmaceutical compositions can also be formulated as modifiedrelease dosage forms, including delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology,2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, N.Y.,2008).

In one embodiment, a pharmaceutical composition provided herein isformulated in a dosage form for oral administration. In one embodiment,an oral pharmaceutical composition provided herein further comprises oneor more pharmaceutically acceptable excipients. In one embodiment, anoral pharmaceutical composition provided herein is formulated as acapsule. In another embodiment, an oral pharmaceutical compositionprovided herein is formulated as a tablet.

In another embodiment, a pharmaceutical composition provided herein isformulated in a dosage form for parenteral administration. In oneembodiment, the parenteral pharmaceutical composition is formulated in adosage form for intravenous administration. In another embodiment, theparenteral pharmaceutical composition is formulated in a dosage form forintramuscular administration. In yet another embodiment, the parenteralpharmaceutical composition is formulated in a dosage form forsubcutaneous administration.

In yet another embodiment, a pharmaceutical composition provided hereinis formulated in a dosage form for topical administration.

In certain embodiments, the pharmaceutical compositions provided hereinare provided in a unit-dosage form or multiple-dosage form. Aunit-dosage form, as used herein, refers to physically discrete a unitsuitable for administration to a human and animal subject, and packagedindividually as is known in the art. Each unit-dose contains apredetermined quantity of an active ingredient(s) sufficient to producethe desired therapeutic effect, in association with the requiredpharmaceutical excipients. Examples of a unit-dosage form include anampoule, syringe, and individually packaged tablet and capsule. Aunit-dosage form may be administered in fractions or multiples thereof.A multiple-dosage form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dosage form. Examples of a multiple-dosage form include a vial,bottle of tablets or capsules, or bottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

In certain embodiments, each active compound in a pharmaceuticalcomposition provided herein is micronized.

A. Oral Administration

A pharmaceutical composition provided herein for oral administration canbe provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), a pharmaceutical composition provided herein cancontain one or more pharmaceutically acceptable carriers or excipients,including, but not limited to, binders, fillers, diluents,disintegrants, wetting agents, lubricants, glidants, coloring agents,dye-migration inhibitors, sweetening agents, flavoring agents,emulsifying agents, suspending and dispersing agents, preservatives,solvents, non-aqueous liquids, organic acids, and sources of carbondioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in apharmaceutical composition provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in a pharmaceutical composition provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; algins; and mixtures thereof. The amount of a disintegrant in apharmaceutical composition provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in a pharmaceutical compositionprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. A pharmaceuticalcomposition provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W. R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. A pharmaceutical compositionprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

A pharmaceutical composition provided herein for oral administration canbe provided as compressed tablets, tablet triturates, chewable lozenges,rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrant inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

A pharmaceutical composition provided herein for oral administration canbe provided as soft or hard capsules, which can be made from gelatin,methylcellulose, starch, or calcium alginate. The hard gelatin capsule,also known as the dry-filled capsule (DFC), consists of two sections,one slipping over the other, thus completely enclosing the activeingredient. The soft elastic capsule (SEC) is a soft, globular shell,such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

A pharmaceutical composition provided herein for oral administration canbe provided in liquid and semisolid dosage forms, including emulsions,solutions, suspensions, elixirs, and syrups. An emulsion is a two-phasesystem, in which one liquid is dispersed in the form of small globulesthroughout another liquid, which can be oil-in-water or water-in-oil.Emulsions may include a pharmaceutically acceptable non-aqueous liquidor solvent, emulsifying agent, and preservative. Suspensions may includea pharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

A pharmaceutical composition provided herein for oral administration canbe also provided in the forms of liposomes, micelles, microspheres, ornanosystems. Micellar dosage forms can be prepared as described in U.S.Pat. No. 6,350,458.

A pharmaceutical composition provided herein for oral administration canbe provided as non-effervescent or effervescent, granules and powders,to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

A pharmaceutical composition provided herein for oral administration canbe formulated as immediate or modified release dosage forms, includingdelayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

A pharmaceutical composition provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

A pharmaceutical composition provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

A pharmaceutical composition intended for parenteral administration caninclude one or more pharmaceutically acceptable carriers and excipients,including, but not limited to, aqueous vehicles, water-misciblevehicles, non-aqueous vehicles, antimicrobial agents or preservativesagainst the growth of microorganisms, stabilizers, solubility enhancers,isotonic agents, buffering agents, antioxidants, local anesthetics,suspending and dispersing agents, wetting or emulsifying agents,complexing agents, sequestering or chelating agents, cryoprotectants,lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When a pharmaceutical composition provided herein is formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical composition for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical composition is provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical composition is provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical composition is provided as sterile dry insoluble productsto be reconstituted with a vehicle prior to use. In still anotherembodiment, the pharmaceutical composition is provided as ready-to-usesterile emulsions.

A pharmaceutical composition provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

A pharmaceutical composition provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, a pharmaceutical composition provided herein is dispersed ina solid inner matrix, which is surrounded by an outer polymeric membranethat is insoluble in body fluids but allows the active ingredient in thepharmaceutical composition diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber, epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

A pharmaceutical composition provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

A pharmaceutical composition provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of a pharmaceutical composition provided herein canalso comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

A pharmaceutical composition provided herein can also be administeredtopically by electroporation, iontophoresis, phonophoresis,sonophoresis, or microneedle or needle-free injection, such asPOWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (BiojectMedical Technologies Inc., Tualatin, Oreg.).

A pharmaceutical composition provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

A pharmaceutical composition provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, ointments, solutions, emulsions,suspensions, tampons, gels, foams, sprays, or enemas. These dosage formscan be manufactured using conventional processes as described inRemington: The Science and Practice of Pharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with a pharmaceuticalcomposition provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

A pharmaceutical composition provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

A pharmaceutical composition provided herein can be administeredintranasally or by inhalation to the respiratory tract. A pharmaceuticalcomposition can be provided in the form of an aerosol or solution fordelivery using a pressurized container, pump, spray, atomizer, such asan atomizer using electrohydrodynamics to produce a fine mist, ornebulizer, alone or in combination with a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Apharmaceutical composition can also be provided as a dry powder forinsufflation, alone or in combination with an inert carrier such aslactose or phospholipids; and nasal drops. For intranasal use, thepowder can comprise a bioadhesive agent, including chitosan orcyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

A pharmaceutical composition provided herein can be micronized to a sizesuitable for delivery by inhalation, such as about 50 micrometers orless, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of a pharmaceuticalcomposition provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. A pharmaceutical composition provided herein forinhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

A pharmaceutical composition provided herein for topical administrationcan be formulated to be immediate release or modified release, includingdelayed-, sustained-, pulsed-, controlled-, targeted, and programmedrelease.

D. Modified Release

A pharmaceutical composition provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. A pharmaceuticalcomposition in modified release dosage forms can be prepared using avariety of modified release devices and methods known to those skilledin the art, including, but not limited to, matrix controlled releasedevices, osmotic controlled release devices, multiparticulate controlledrelease devices, ion-exchange resins, enteric coatings, multilayeredcoatings, microspheres, liposomes, and combinations thereof. The releaserate of the active ingredient(s) can also be modified by varying theparticle sizes and polymorphism of the active ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

A pharmaceutical composition provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, a pharmaceutical composition provided herein ina modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, a pharmaceutical composition provided herein isformulated with a non-erodible matrix device. The active ingredient(s)is dissolved or dispersed in an inert matrix and is released primarilyby diffusion through the inert matrix once administered. Materialssuitable for use as a non-erodible matrix device include, but are notlimited to, insoluble plastics, such as polyethylene, polypropylene,polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinyl chloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcoholcopolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

A pharmaceutical composition provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

A pharmaceutical composition provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can be substantially modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

A pharmaceutical composition in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, a pharmaceutical composition provided herein isformulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, a pharmaceutical composition provided herein isformulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

A pharmaceutical composition provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with apharmaceutical composition provided herein to aid in processing andforming the multiparticulates. The resulting particles can themselvesconstitute the multiparticulate device or can be coated by variousfilm-forming materials, such as enteric polymers, water-swellable, andwater-soluble polymers. The multiparticulates can be further processedas a capsule or a tablet.

4. Targeted Delivery

A pharmaceutical composition provided herein can also be formulated tobe targeted to a particular tissue, receptor, or other area of the bodyof the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided herein is a method of treating, preventing,or ameliorating one or more symptoms of a cardiovascular disease in asubject, comprising administering to the subject two or more compounds,wherein each compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In certain embodiments, the cardiovascular disease is acute myocardialinfarction, aortic aneurysms, atherosclerosis, atherosclerosis, atrialfibrillation, atrial flutter, cardiomyopathy, carditis, acerebrovascular disease, chest pain (angina), a congenital heartdisease, a coronary artery disease, endocarditis, hemorrhagic stroke,heart arrhythmia, heart attack, heart block, heart failure, ahypertensive heart disease, an ischemic heart disease, ischemic stroke,left ventricular dysfunction, myocardial fibrosis, myocardial infarction(heart attack), myocardial ischemia, myocarditis, a peripheral arterydisease, a peripheral vascular disease, a rheumatic heart disease,stroke, a valvular heart disease, or venous thrombosis.

In one embodiment, the cardiovascular disease is heart attack. Inanother embodiment, the cardiovascular disease is heart failure. In yetanother embodiment, the cardiovascular disease is heart failureassociated with abnormal cardiac output. In yet another embodiment, thecardiovascular disease is stroke. In yet another embodiment, thecardiovascular disease is cardiac arrhythmia. In still anotherembodiment, the cardiovascular disease is venous thrombosis.

In one embodiment, the cardiovascular disease is cardiac arrhythmia. Inanother embodiment, the cardiovascular disease is bradycardia. In yetanother embodiment, cardiovascular disease is sinus bradycardia, sinusarrest, sinus exit block, atrioventricular (AV) block. In still anotherembodiment, cardiovascular disease is severe sinus bradycardia,sinoatrial block, sinus arrest, or bradycardia-tachycardia syndrome.

In certain embodiments, the cardiovascular disease is heart block. Incertain embodiments, the heart block is AV block. In certainembodiments, the AV block is first-degree, second-degree, orthird-degree AV block. In certain embodiments, the AV block is Mobitztype I or II second-degree AV block.

In another embodiment, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of bradycardia in asubject, comprising administering to the subject two or more compounds,wherein each compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the bradycardia is atrial bradycardia,atrioventricular nodal bradycardia, infantile bradycardia, orventricular bradycardia. In another embodiment, the bradycardia isrespiratory sinus arrhythmia, sinus bradycardia, or sick sinus (SS)bradycardia.

In one embodiment, the bradycardia is asymptomatic bradycardia. Inanother embodiment, the bradycardia is symptomatic bradycardia.

In one embodiment, the bradycardia is early stage bradycardia. Inanother embodiment, the bradycardia is severe bradycardia. In oneembodiment, the bradycardia is symptomatic bradycardia due to sick sinussymptom.

In certain embodiments, the bradycardia is associated with AV block. Incertain embodiments, the bradycardia is associated with first-degree,second-degree, or third-degree AV block. In certain embodiments, thebradycardia is associated with Mobitz type I or II second-degree AVblock.

In certain embodiments, the subject to be treated with a pharmaceuticalcomposition or method provided herein does not have chronic obstructivepulmonary disease.

In certain embodiments, the subject after being treated with apharmaceutical composition or method provided herein has an increase inresting pulse rate from about 28-45 BPM to about 40-68 BPM.

In yet another embodiment, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of stroke in a subject,comprising administering to the subject two or more compounds, whereineach compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the stroke is hemorrhagic stroke. In anotherembodiment, the stroke is ischemic stroke. In yet another embodiment,the stroke is stroke associated with abnormal cardiac output. In stillanother embodiment, the stroke is stroke associated with bradycardia.

In yet another embodiment, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of cerebral vascularthrombosis in a subject, comprising administering to the subject two ormore compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

Without being bound by any theory, a subject normally has slower heartbeats when sleeping at night. Consequently, a bradycardia subject isprone to thrombosis during sleeping because of the slower heart beats.

In yet another embodiment, provided herein is a method of treating,preventing, or ameliorating abnormal heart rhythm (e.g., heart rate≤50beats per minutes (BPM)) in a subject after a cardiac surgery,comprising administering to the subject two or more compounds, whereineach compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, the subject after being treated with a pharmaceuticalcomposition or method provided herein has a normal heart rhythm. In oneembodiment, the subject after being treated with a pharmaceuticalcomposition or method provided herein has a resting pulse rate (RPR)ranging from about 35 to about 130, from about 40 to about 120, fromabout 45 to 110, from about 50 to about 100, or from about 60 to about100. In another embodiment, the subject after being treated with apharmaceutical composition or method provided herein has a RPR of about40, about 42, about 44, about 46, about 48, about 50, about 52, about54, about 56, about 58, about 60, about 62, about 64, about 66, about68, or about 70. In yet another embodiment, the subject after beingtreated with a pharmaceutical composition or method provided herein hasa RPR of about 51, about 52, about 53, about 54, about 55, about 56,about 57, about 58, about 59, about 60, about 61, about 62, about 63,about 64, about 65, about 66, about 67, about 68, about 69, about 70,about 71, about 72, about 73, about 74, or about 75.

In yet another embodiment, provided herein is a method of increasingheart rate in a subject, comprising administering to the subject two ormore compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, provided herein is a method of increasing heart ratewithout a substantial change in oxygen consumption in a subject,comprising administering to the subject: (i) a phosphodiesteraseinhibitor or an adenosine receptor antagonist; and (ii) a calciumchannel blocker.

In another embodiment, provided herein is a method of increasing heartrate without a substantial change in oxygen consumption in a subject,comprising administering to the subject: (i) a xanthine compound or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In yet another embodiment, provided herein is a method of increasingheart rate without a substantial change in oxygen consumption in asubject, comprising administering to the subject: (i) theophylline or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) nifedipine or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof.

In still another embodiment, provided herein is a method of increasingheart rate without a substantial change in oxygen consumption in asubject, comprising administering to the subject: (i) aminophylline ortheophylline; and (ii) nifedipine.

Without being bound by any theory, a phosphodiesterase inhibitor oradenosine receptor antagonist can be paired together with a calciumchannel blocker to minimize undesired side effect(s). For example,theophylline is known to have the side effect of causing an increase inoxygen consumption, whereas nifedipine is known to have the side effectof causing a decrease in oxygen consumption. Both are also known to havethe side effect of causing an increase in heart rate. Thus, theophyllinecan be paired together with nifedipine to cause an increase in heartrate without a substantial change in oxygen consumption.

In one embodiment, provided herein is a method of increasing heart ratewithout a substantial change in blood pressure in a subject, comprisingadministering to the subject: (i) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist;and (ii) a β₂-adrenoreceptor agonist; wherein the subject has nosubstantial change in blood pressure.

In another embodiment, provided herein is a method of increasing heartrate without a substantial change in blood pressure in a subject,comprising administering to the subject: (i) betahistine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) albuterol, or an enantiomer, a mixture ofenantiomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.

In yet another embodiment, provided herein is a method of increasingheart rate without a substantial change in blood pressure in a subject,comprising administering to the subject: (i) betahistine hydrochloride;and (ii) albuterol hydrochloride or levalbuterol hydrochloride.

Without being bound by any theory, a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist canbe paired together with a β₂-adrenoreceptor agonist to minimizeundesired side effect(s). For example, betahistine is known to have theside effect of causing an increase in blood pressure, whereas albuteroland levalbuterol are each known to have the side effect of causing adecrease in blood pressure. Betahistine, albuterol, and levalbuterol arealso known to have the side effect of causing an increase in heart rate.Thus, betahistine can be paired together with albuterol or levalbuterolto cause an increase in heart rate without a substantial change in bloodpressure.

In one embodiment, the subject after treated with a pharmaceuticalcomposition or method provided herein has an increase in a RPR rangingfrom about 2 to about 25, from about 5 to about 20, from about 5 toabout 15, or from about 5 to about 10. In another embodiment, thesubject after treated with a pharmaceutical composition or methodprovided herein has an increase in a RPR of about 5, about 6, about 7,about 8, about 9, or about 10.

In yet another embodiment, provided herein is a method of increasingcardiac output in a subject, comprising administering to the subject twoor more compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, the subject after being treated with a pharmaceuticalcomposition or method provided herein has an increase in cardiac outputat rest ranging from about 200 to about 2,000, from about 100 to about1,000, or from about 100 to about 500 mL/min.

In yet another embodiment, provided herein is a method of increasingcerebral blood flow in a subject, comprising administering to thesubject two or more compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, the subject after being treated with a pharmaceuticalcomposition or method provided herein has an increase in cerebral bloodflow ranging from about 200 to about 750, from about 250 to about 600,or from about 300 to about 500 mL/min.

In one embodiment, a method provided herein comprises administering tothe subject two compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist; and (ii) a calcium channel blocker. In another embodiment, amethod provided herein comprises administering to the subject: (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; and(ii) a histamine H₁-receptor agonist, a histamine H₂-receptor agonist,or a histamine H₃-receptor antagonist. In yet another embodiment, amethod provided herein comprises administering to the subject: (i) aphosphodiesterase inhibitor or an adenosine receptor antagonist; and(ii) a β₂-adrenoreceptor agonist. In yet another embodiment, a methodprovided herein comprises administering to the subject: (i) a calciumchannel blocker; and (ii) a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist. In yetanother embodiment, a method provided herein comprises administering tothe subject: (i) a calcium channel blocker and (ii) a β₂-adrenoreceptoragonist. In still another embodiment, a method provided herein comprisesadministering to the subject: (i) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist;and (ii) a β₂-adrenoreceptor agonist.

In another embodiment, a method provided herein comprises administeringto the subject three compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, a calciumchannel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist; (ii) a calcium channel blocker; and (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist. In another embodiment, a method provided hereincomprises administering to the subject: (i) a phosphodiesteraseinhibitor or an adenosine receptor antagonist; (ii) a calcium channelblocker; and (iii) a β₂-adrenoreceptor agonist. In yet anotherembodiment, a method provided herein comprises administering to thesubject: (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist; (ii) a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist; and (iii) aβ₂-adrenoreceptor agonist.

In yet another embodiment, a method provided herein comprisesadministering to the subject four compounds, wherein each compound isindependently a phosphodiesterase inhibitor, an adenosine receptorantagonist, a calcium channel blocker, a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, a histamine H₃-receptor antagonist, ora β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a phosphodiesterase inhibitor or an adenosine receptorantagonist; (ii) a calcium channel blocker; (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist; and (iv) β₂-adrenoreceptor agonist.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the calcium channelblocker in a method provided herein is ranging from about 1 to about180, from about 2 to about 100, from about 2 to about 50, or from about2 to about 20. In certain embodiments, the weight ratio of (i) thephosphodiesterase inhibitor or adenosine receptor antagonist to (ii) thecalcium channel blocker in a method provided herein is about 2, about 3,about 4, about 5, about 6, about 7, about 8, about 9, about 10, about11, about 12, about 13, about 14, about 15, about 16, about 17, about18, about 19, or about 20.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist in a method provided herein is ranging from about2 to about 200, from about 4 to about 100, from about 5 to about 50, orfrom about 10 to about 30. In certain embodiments, the weight ratio of(i) the phosphodiesterase inhibitor or adenosine receptor antagonist to(ii) the histamine H₁-receptor agonist, histamine H₂-receptor agonist,or histamine H₃-receptor antagonist in a method provided herein is about10, about 12, about 14, about 16, about 18, about 20, about 22, about24, about 26, about 28, or about 30.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the β₂-adrenoreceptoragonist in a method provided herein is ranging from about 1 to about1,000, from about 10 to about 500, from about 20 to about 400, or fromabout 40 to about 300. In certain embodiments, the weight ratio of (i)the phosphodiesterase inhibitor or adenosine receptor antagonist to (ii)the β₂-adrenoreceptor agonist in a method provided herein is about 40,about 60, about 80, about 100, about 120, about 140, about 160, about180, about 200, about 220, about 240, about 260, about 280, or about300.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) the histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist in a method provided hereinis ranging from about 1 to about 50, from about 1 to about 40, fromabout 1 to about 20, or from about 1 to about 10. In certainembodiments, the weight ratio of (i) the calcium channel blocker to (ii)the histamine H₁-receptor agonist, histamine H₂-receptor agonist, orhistamine H₃-receptor antagonist in a method provided herein is about 1,about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5,about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8,about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) the β₂-adrenoreceptor agonist in a method providedherein is ranging from about 1 to about 100, from about 5 to about 50,or from about 5 to about 30. In certain embodiments, the weight ratio of(i) the calcium channel blocker to (ii) the β₂-adrenoreceptor agonist ina method provided herein is about 5, about 6, about 8, about 10, about12, about 14, about 16, about 18, about 20, about 22, about 24, about26, about 28, or about 20.

In certain embodiments, the weight ratio of (i) the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist to (ii) the β₂-adrenoreceptor agonist in a methodprovided herein is ranging from about 1 to about 100, from about 1 toabout 50, from about 1 to about 30, or from about 1 to about 20. Incertain embodiments, the weight ratio of (i) the histamine H₁-receptoragonist, histamine H₂-receptor agonist, or histamine H₃-receptorantagonist to (ii) the β₂-adrenoreceptor agonist in a method providedherein is about 1, about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 11, about 12, about 13, about 14,about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, a method provided herein comprises administeringto the subject a phosphodiesterase inhibitor or an adenosine receptorantagonist in a subtherapeutic effective amount. In certain embodiments,a method provided herein comprises administering to the subject aphosphodiesterase inhibitor or an adenosine receptor antagonist in theamount ranging from about 1 to about 1,200, from about 5 to about 1,000,from about 10 to about 800, or from about 20 to about 600 mg per day. Incertain embodiments, a method provided herein comprises administering tothe subject a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 1 to about 1,200 mg per day.In certain embodiments, a method provided herein comprises administeringto the subject a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 5 to about 1,000 mg per day.In certain embodiments, a method provided herein comprises administeringto the subject a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 10 to about 800 mg per day.In certain embodiments, a method provided herein comprises administeringto the subject a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount ranging from about 20 to about 600 mg per day.In certain embodiments, a method provided herein comprises administeringto the subject a phosphodiesterase inhibitor or an adenosine receptorantagonist in the amount of about 20, about 50, about 75, about 100,about 125, about 150, about 175, about 200, about 225, about 250, about275, about 300, about 325, about 350, about 375, about 400, about 425,about 450, about 475, about 500, about 525, about 550, about 575, orabout 600 mg per day.

In certain embodiments, a method provided herein comprises administeringto the subject a calcium channel blocker in a subtherapeutic effectiveamount. In certain embodiments, a method provided herein comprisesadministering to the subject a calcium channel blocker in the amountranging from about 1 to about 200, from about 1 to about 100, or fromabout 2 to about 60 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject a calcium channelblocker in the amount ranging from about 1 to about 200 mg per day. Incertain embodiments, a method provided herein comprises administering tothe subject a calcium channel blocker in the amount ranging from about 1to about 100 mg per day. In certain embodiments, a method providedherein comprises administering to the subject a calcium channel blockerin the amount ranging from about 2 to about 60 mg per day. In certainembodiments, a method provided herein comprises administering to thesubject a calcium channel blocker in the amount of about 2, about 5,about 10, about 15, about 20, about 25, about 30, about 35, about 40,about 45, about 50, about 55, or about 60 mg per day.

In certain embodiments, a method provided herein comprises administeringto the subject a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist in a subtherapeuticeffective amount. In certain embodiments, a method provided hereincomprises administering to the subject a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, or a histamine H₃-receptor antagonistin the amount ranging from about 0.1 to about 100, from about 0.5 toabout 50, from about 1 to about 30 mg per day. In certain embodiments, amethod provided herein comprises administering to the subject ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist in the amount ranging from about 0.1 toabout 100 mg per day. In certain embodiments, a method provided hereincomprises administering to the subject a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, or a histamine H₃-receptor antagonistin the amount ranging from about 0.5 to about 50 mg per day. In certainembodiments, a method provided herein comprises administering to thesubject a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist in the amount rangingfrom about 1 to about 30 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist in the amount of about 1, about 2, about 4, about6, about 8, about 10, about 12, about 14, about 16, about 18, about 20,about 22, about 24, about 26, about 28 or about 30 mg per day.

In certain embodiments, a method provided herein comprises administeringto the subject a β₂-adrenoreceptor agonist in a subtherapeutic effectiveamount. In certain embodiments, a method provided herein comprisesadministering to the subject a β₂-adrenoreceptor agonist in the amountranging from about 0.1 to about 50, from about 0.1 to about 20, or fromabout 0.1 to about 10 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject aβ₂-adrenoreceptor agonist in the amount ranging from about 0.1 to about50 mg per day. In certain embodiments, a method provided hereincomprises administering to the subject a β₂-adrenoreceptor agonist inthe amount ranging from about 0.1 to about 20 mg per day. In certainembodiments, a method provided herein comprises administering to thesubject a β₂-adrenoreceptor agonist in the amount ranging from about 0.1to about 10 mg per day. In certain embodiments, a method provided hereincomprises administering to the subject a β₂-adrenoreceptor agonist inthe amount of about 0.1, about 0.2, about 0.5, about 1, about 1.5, about2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 6,about 7, about 8, about 9, or about 10 mg per day.

In certain embodiments, the phosphodiesterase inhibitor or adenosinereceptor antagonist in a method provided herein is administered oncedaily (QD) or divided into multiple daily doses such as twice daily(BID), three times daily (TID), four times daily (QID), five timesdaily, or six times daily. In certain embodiments, the phosphodiesteraseinhibitor or adenosine receptor antagonist in a method provided hereinis administered QD. In certain embodiments, the phosphodiesteraseinhibitor or adenosine receptor antagonist in a method provided hereinis administered BID. In certain embodiments, the phosphodiesteraseinhibitor or adenosine receptor antagonist in a method provided hereinis administered TID. In certain embodiments, the phosphodiesteraseinhibitor or adenosine receptor antagonist in a method provided hereinis administered QID.

In certain embodiments, the calcium channel blocker in a method providedherein is administered once daily (QD) or divided into multiple dailydoses such as twice daily (BID), three times daily (TID), four timesdaily (QID), five times daily, or six times daily. In certainembodiments, the calcium channel blocker in a method provided herein isadministered QD. In certain embodiments, the calcium channel blocker ina method provided herein is administered BID. In certain embodiments,the calcium channel blocker in a method provided herein is administeredTID. In certain embodiments, the calcium channel blocker in a methodprovided herein is administered QID.

In certain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist in a methodprovided herein is administered once daily (QD) or divided into multipledaily doses such as twice daily (BID), three times daily (TID), fourtimes daily (QID), five times daily, or six times daily. In certainembodiments, the histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist in a method provided hereinis administered QD. In certain embodiments, the histamine H₁-receptoragonist, histamine H₂-receptor agonist, or histamine H₃-receptorantagonist in a method provided herein is administered BID. In certainembodiments, the histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist in a method provided hereinis administered TID. In certain embodiments, the histamine H₁-receptoragonist, histamine H₂-receptor agonist, or histamine H₃-receptorantagonist in a method provided herein is administered QID.

In certain embodiments, the β₂-adrenergic receptor agonist in a methodprovided herein is administered once daily (QD), or divided intomultiple daily doses such as twice daily (BID), three times daily (TID),four times daily (QID), five times daily, or six times daily. In certainembodiments, the β₂-adrenergic receptor agonist in a method providedherein is administered QD. In certain embodiments, the β₂-adrenergicreceptor agonist in a method provided herein is administered BID. Incertain embodiments, the β₂-adrenergic receptor agonist in a methodprovided herein is administered TID. In certain embodiments, theβ₂-adrenergic receptor agonist in a method provided herein isadministered QID.

In certain embodiments, the phosphodiesterase inhibitor, adenosinereceptor antagonist, calcium channel blocker, histamine H₁-receptoragonist, histamine H₂-receptor agonist, or histamine H₃-receptorantagonist, and β₂-adrenoreceptor agonist in a method provided hereinare administered concurrently or sequentially in any order. In certainembodiments, the phosphodiesterase inhibitor and/or adenosine receptorantagonist in a method provided herein is administered currently withthe calcium channel blocker. In certain embodiments, thephosphodiesterase inhibitor and/or adenosine receptor antagonist in amethod provided herein is administered currently with the calciumchannel blocker in a single pharmaceutical composition provided herein.In certain embodiments, the histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist in a methodprovided herein is administered concurrently with the β₂-adrenoreceptoragonist. In certain embodiments, the histamine H₁-receptor agonist,histamine H₂-receptor agonist, or histamine H₃-receptor antagonist in amethod provided herein is administered concurrently with theβ₂-adrenoreceptor agonist in a single pharmaceutical compositionprovided herein. In certain embodiments, the phosphodiesteraseinhibitor, adenosine receptor antagonist, calcium channel blocker,histamine H₁-receptor agonist, histamine H₂-receptor agonist, orhistamine H₃-receptor antagonist, and β₂-adrenoreceptor agonist in amethod provided herein are administered concurrently. In certainembodiments, the phosphodiesterase inhibitor, adenosine receptorantagonist, calcium channel blocker, histamine H₁-receptor agonist,histamine H₂-receptor agonist, or histamine H₃-receptor antagonist, andβ₂-adrenoreceptor agonist in a method provided herein are administeredin a single pharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) one or more compounds, wherein each compound is independently acalcium channel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) a xanthine compound or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) a calcium channel blocker, a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) a calcium channel blocker. In another embodiment, a method providedherein comprises administering to the subject: (i) a xanthine compoundor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or histamine H₃-receptor antagonist. Inyet another embodiment, a method provided herein comprises administeringto the subject: (i) a xanthine compound or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) a β₂-adrenoreceptor agonist.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) two compounds, wherein each compound isindependently a calcium channel blocker, a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, a histamine H₃-receptorantagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) acalcium channel blocker; and (iii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or histamine H₃-receptor antagonist. Inanother embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) acalcium channel blocker; and (iii) a β₂-adrenoreceptor agonist. In yetanother embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist; and (iii) a β₂-adrenoreceptor agonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) three compounds, wherein each compound isindependently a calcium channel blocker, a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, a histamine H₃-receptorantagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) acalcium channel blocker; (iii) a histamine H₁-receptor agonist, ahistamine H₂-receptor agonist, or a histamine H₃-receptor antagonist;and (iv) a β₂-adrenoreceptor agonist.

In certain embodiments, the weight ratio of the xanthine compound to thecalcium channel blocker in a method provided herein is ranging fromabout 1 to about 180, from about 2 to about 100, from about 2 to about50, or from about 2 to about 20. In certain embodiments, the weightratio of the xanthine compound to the calcium channel blocker in amethod provided herein is ranging from about 1 to about 180. In certainembodiments, the weight ratio of the xanthine compound to the calciumchannel blocker in a method provided herein is ranging from about 2 toabout 100. In certain embodiments, the weight ratio of the xanthinecompound to the calcium channel blocker in a method provided herein isranging from about 2 to about 50. In certain embodiments, the weightratio of the xanthine compound to the calcium channel blocker in amethod provided herein is ranging from about 2 to about 20. In certainembodiments, the weight ratio of the xanthine compound to the calciumchannel blocker in a method provided herein is about 2, about 4, about6, about 8, about 10, about 12, about 14, about 16, about 18, or about20.

In certain embodiments, the weight ratio of (i) the xanthine compound to(ii) the histamine H₁-receptor agonist, histamine H₂-receptor agonist,or histamine H₃-receptor antagonist in a method provided herein isranging from about 2 to about 200, from about 4 to about 100, from about5 to about 50, or from about 10 to about 30. In certain embodiments, theweight ratio of (i) the xanthine compound to (ii) the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist in a method provided herein is about 10, about12, about 14, about 16, about 18, about 20, about 22, about 24, about26, about 28, or about 30.

In certain embodiments, the weight ratio of the xanthine compound to theβ₂-adrenoreceptor agonist in a method provided herein is ranging fromabout 1 to about 1,000, from about 10 to about 500, from about 20 toabout 400, or from about 40 to about 300. In certain embodiments, theweight ratio of the xanthine compound to the β₂-adrenoreceptor agonistin a method provided herein is about 40, about 60, about 80, about 100,about 120, about 140, about 160, about 180, about 200, about 220, about240, about 260, about 280, or about 300.

In certain embodiments, a method provided herein comprises administeringto the subject a xanthine compound or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof in asubtherapeutic effective amount. In certain embodiments, a methodprovided herein comprises administering to the subject a xanthinecompound in the amount ranging from about 1 to about 1,200, from about 5to about 1,000, from about 10 to about 800, or from about 20 to about600 mg per day. In certain embodiments, a method provided hereincomprises administering to the subject a xanthine compound in the amountranging from about 1 to about 1,200 mg per day. In certain embodiments,a method provided herein comprises administering to the subject axanthine compound in the amount ranging from about 5 to about 1,000 mgper day. In certain embodiments, a method provided herein comprisesadministering to the subject a xanthine compound in the amount rangingfrom about 10 to about 800 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject a xanthinecompound in the amount ranging from about 20 to about 600 mg per day. Incertain embodiments, a method provided herein comprises administering tothe subject a xanthine compound in the amount of about 20, about 50,about 75, about 100, about 125, about 150, about 175, about 200, about225, about 250, about 275, about 300, about 325, about 350, about 375,about 400, about 425, about 450, about 475, about 500, about 525, about550, about 575, or about 600 mg per day.

In certain embodiments, the xanthine compound in a method providedherein is administered once daily (QD), or divided into multiple dailydoses such as twice daily (BID), three times daily (TID), four timesdaily (QID), five times daily, or six times daily. In certainembodiments, the xanthine compound in a method provided herein isadministered QD. In certain embodiments, the xanthine compound in amethod provided herein is administered BID. In certain embodiments, thexanthine compound in a method provided herein is administered TID. Incertain embodiments, the xanthine compound in a method provided hereinis administered QID.

In certain embodiments, the xanthine compound in a method providedherein is administered concurrently or sequentially in any order withthe calcium channel blocker, histamine H₁-receptor agonist, histamineH₂-receptor agonist, histamine H₃-receptor antagonist, andβ₂-adrenoreceptor agonist. In certain embodiments, the xanthine compoundin a method provided herein is administered concurrently with thecalcium channel blocker. In certain embodiments, the xanthine compoundin a method provided herein is administered concurrently with thecalcium channel blocker in a single pharmaceutical composition providedherein. In certain embodiments, the xanthine compound in a methodprovided herein is administered concurrently with the calcium channelblocker, histamine H₁-receptor agonist, histamine H₂-receptor agonist,histamine H₃-receptor antagonist, and β₂-adrenoreceptor agonist. Incertain embodiments, the xanthine compound in a method provided hereinis administered concurrently with the calcium channel blocker, histamineH₁-receptor agonist, histamine H₂-receptor agonist, histamineH₃-receptor antagonist, and β₂-adrenoreceptor agonist in a singlepharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)one or more compounds, wherein each compound is independently a PDEinhibitor, an adenosine receptor antagonist, a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, a histamine H₃-receptorantagonist or a β₂-adrenoreceptor agonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) a dihydropyridine or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) a PDE inhibitor, an adenosine receptor antagonist, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a PDE inhibitor or an adenosine receptor antagonist. In anotherembodiment, a method provided herein comprises administering to thesubject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a histamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist. In yet another embodiment, a methodprovided herein comprises administering to the subject: (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) aβ₂-adrenoreceptor agonist.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) two compounds, wherein each compound isindependently a PDE inhibitor, an adenosine receptor antagonist, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, ahistamine H₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) aPDE inhibitor or an adenosine receptor antagonist; and (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist. In another embodiment, a method provided hereincomprises administering to the subject: (i) a dihydropyridine or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) a PDE inhibitor or an adenosinereceptor antagonist; and (iii) a β₂-adrenoreceptor agonist. In yetanother embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist;

and (iii) a β₂-adrenoreceptor agonist.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) three compounds, wherein each compound isindependently a PDE inhibitor, an adenosine receptor antagonist, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, ahistamine H₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) aPDE inhibitor or an adenosine receptor antagonist; (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist; and (iv) a β₂-adrenoreceptor agonist.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) the dihydropyridinein a method provided herein is ranging from about 1 to about 180, fromabout 2 to about 100, from about 2 to about 50, or from about 2 to about20. In certain embodiments, the weight ratio of (i) thephosphodiesterase inhibitor or adenosine receptor antagonist to (ii) thedihydropyridine in a method provided herein is about 2, about 4, about6, about 8, about 10, about 12, about 14, about 16, about 18, or about20.

In certain embodiments, the weight ratio of (i) the dihydropyridine to(ii) the histamine H₁-receptor agonist, histamine H₂-receptor agonist,or histamine H₃-receptor antagonist in a method provided herein isranging from about 1 to about 50, from about 1 to about 40, from about 1to about 20, or from about 1 to about 10. In certain embodiments, theweight ratio of (i) the dihydropyridine to (ii) the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist in a method provided herein is about 1, about1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about8.5, about 9, about 9.5, or about 10.

In certain embodiments, the weight ratio of the dihydropyridine to theβ₂-adrenoreceptor agonist in a method provided herein is ranging fromabout 1 to about 100, from about 1 to about 50, or from about 5 to about30. In certain embodiments, the weight ratio of the dihydropyridine tothe β₂-adrenoreceptor agonist in a method provided herein is about 5,about 10, about 11, about 12, about 13, about 14, about 15, about 16,about 17, about 18, about 19, about 20, about 21, about 22, about 23,about 24, about 25, about 26, about 27, about 28, about 29, or about 30.

In certain embodiments, a method provided herein comprises administeringto the subject a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof in asubtherapeutically effective amount. In certain embodiments, a methodprovided herein comprises administering to the subject a dihydropyridinein a subtherapeutic effective amount. In certain embodiments, a methodprovided herein comprises administering to the subject a dihydropyridinein the amount ranging from about 0.5 to about 200, from about 1 to about100, or from about 2 to about 60 mg per day. In certain embodiments, amethod provided herein comprises administering to the subject adihydropyridine in the amount ranging from about 0.5 to about 200 mg perday. In certain embodiments, a method provided herein comprisesadministering to the subject a dihydropyridine in the amount rangingfrom about 1 to about 100 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject a dihydropyridinein the amount ranging from about 2 to about 50 mg per day. In certainembodiments, a method provided herein comprises administering to thesubject a dihydropyridine in the amount of about 2, about 5, about 10,about 15, about 20, about 25, about 30, about 35, about 40, about 45,about 50, about 55, or about 60 mg per day.

In certain embodiments, the dihydropyridine in a method provided hereinis administered once daily (QD) or divided into multiple daily dosessuch as twice daily (BID), three times daily (TID), four times daily(QID), five times daily, or six times daily. In certain embodiments, thedihydropyridine in a method provided herein is administered QD. Incertain embodiments, the dihydropyridine in a method provided herein isadministered BID. In certain embodiments, the dihydropyridine in amethod provided herein is administered TID. In certain embodiments, thedihydropyridine in a method provided herein is administered QID.

In certain embodiments, the dihydropyridine in a method provided hereinis administered concurrently or sequentially in any order with thephosphodiesterase inhibitor, adenosine receptor antagonist, histamineH₁-receptor agonist, histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or β₂-adrenoreceptor agonist. In certainembodiments, the dihydropyridine in a method provided herein isadministered concurrently with the phosphodiesterase inhibitor oradenosine receptor antagonist. In certain embodiments, thedihydropyridine in a method provided herein is administered concurrentlywith the phosphodiesterase inhibitor or adenosine receptor antagonist ina single pharmaceutical composition provided herein. In certainembodiments, the dihydropyridine in a method provided herein isadministered concurrently with the phosphodiesterase inhibitor,adenosine receptor antagonist, histamine H₁-receptor agonist, histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, orβ₂-adrenoreceptor agonist. In certain embodiments, the dihydropyridinein a method provided herein is administered concurrently with thephosphodiesterase inhibitor, adenosine receptor antagonist, histamineH₁-receptor agonist, histamine H₂-receptor agonist, a histamineH₃-receptor antagonist or β₂-adrenoreceptor agonist in a singlepharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (iii) optionally oneor more compounds, wherein each compound is independently a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) a xanthine compound or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) a dihydropyridine or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and(iii) a histamine H₁-receptor agonist, a histamine H₂-receptor agonist,a histamine H₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist. In another embodiment, a method provided hereincomprises administering to the subject: (i) a xanthine compound or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a β₂-adrenoreceptor agonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) a dihydropyridine or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and(iii) two compounds, wherein each compound is independently a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, a histamineH₃-receptor antagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist; and (iv) a β₂-adrenoreceptor agonist.

In certain embodiments, the weight ratio of the xanthine compound to thedihydropyridine in a method provided herein is ranging from about 1 toabout 180, from about 2 to about 100, from about 2 to about 50, or fromabout 2 to about 20. In certain embodiments, the weight ratio of thexanthine compound to the dihydropyridine in a method provided herein isranging from about 1 to about 180. In certain embodiments, the weightratio of the xanthine compound to the dihydropyridine in a methodprovided herein is ranging from about 2 to about 100. In certainembodiments, the weight ratio of the xanthine compound to thedihydropyridine in a method provided herein is ranging from about 2 toabout 50. In certain embodiments, the weight ratio of the xanthinecompound to the dihydropyridine in a method provided herein is rangingfrom about 2 to about 20. In certain embodiments, the weight ratio ofthe xanthine compound to the dihydropyridine in a method provided hereinis about 2, about 4, about 6, about 8, about 10, about 12, about 14,about 16, about 18, or about 20.

In certain embodiments, the dihydropyridine in a method provided hereinis administered concurrently or sequentially in any order with thexanthine compound, histamine H₁-receptor agonist, histamine H₂-receptoragonist, histamine H₃-receptor antagonist, or β₂-adrenoreceptor agonist.In certain embodiments, the dihydropyridine in a method provided hereinis administered concurrently with the xanthine compound. In certainembodiments, the dihydropyridine in a method provided herein isadministered concurrently with the xanthine compound in a singlepharmaceutical composition provided herein. In certain embodiments, thedihydropyridine in a method provided herein is administered concurrentlywith the xanthine compound, histamine H₁-receptor agonist, histamineH₂-receptor agonist, a histamine H₃-receptor antagonist, or aβ₂-adrenoreceptor agonist. In certain embodiments, the dihydropyridinein a method provided herein is administered concurrently with thexanthine compound, histamine H₁-receptor agonist, histamine H₂-receptoragonist, a histamine H₃-receptor antagonist, or β₂-adrenoreceptoragonist in a single pharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) one or more compounds, wherein each compoundis independently a PDE inhibitor, an adenosine receptor antagonist, acalcium channel blocker, or a β₂-adrenergic receptor agonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) a PDE inhibitor, an adenosine receptorantagonist, a calcium channel blocker, and a β₂-adrenergic receptoragonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) a PDE inhibitor or an adenosine receptorantagonist. In another embodiment, a method provided herein comprisesadministering to the subject: (i) betahistine, a metabolite thereof, oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) a calcium channel blocker. In yetanother embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) a β₂-adrenergic receptor agonist.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) betahistine, a metabolite thereof, oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) two compounds, wherein eachcompound is independently a PDE inhibitor, an adenosine receptorantagonist, a calcium channel blocker, or a β₂-adrenergic receptoragonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) a PDE inhibitor or adenosine receptor antagonist;and (iii) a calcium channel blocker. In another embodiment, a methodprovided herein comprises administering to the subject: (i) betahistine,a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) aPDE inhibitor or adenosine receptor antagonist; and (iii) aβ₂-adrenergic receptor agonist. In yet another embodiment, a methodprovided herein comprises administering to the subject: (i) betahistine,a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) acalcium channel blocker; and (iii) a β₂-adrenergic receptor agonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) betahistine, a metabolite thereof, oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) three compounds, wherein eachcompound is independently a PDE inhibitor, an adenosine receptorantagonist, a calcium channel blocker, or a β₂-adrenergic receptoragonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) a PDE inhibitor or an adenosine receptorantagonist; (iii) a calcium channel blocker; and (iv) a β₂-adrenergicreceptor agonist.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) betahistine in amethod provided herein is ranging from about 2 to about 200, from about4 to about 100, from about 5 to about 50, or from about 10 to about 30.In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) betahistine in amethod provided herein is about 10, about 11, about 12, about 13, about14, about 15, about 16, about 17, about 18, about 19, about 20, about21, about 22, about 23, about 24, about 25, about 26, about 27, about28, about 29, or about 30.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) betahistine in a method provided herein is ranging fromabout 1 to about 50, from about 1 to about 40, from about 1 to about 20,or from about 1 to about 10. In certain embodiments, the weight ratio of(i) the calcium channel blocker to (ii) betahistine in a method providedherein is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5,about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7,about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, the weight ratio of (i) betahistine to (ii) theβ₂-adrenoreceptor agonist in a method provided herein is ranging fromabout 1 to about 100, from about 1 to about 50, from about 1 to about30, or from about 1 to about 20. In certain embodiments, the weightratio of (i) betahistine to (ii) the β₂-adrenoreceptor agonist in amethod provided herein is about 1, about 2, about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10, about 11, about 12, about13, about 14, about 15, about 16, about 17, about 18, about 19, or about20.

In certain embodiments, a method provided herein comprises administeringto the subject betahistine, a metabolite thereof, or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof in a subtherapeutically effective amount. In certainembodiments, a method provided herein comprises administering to thesubject betahistine in the amount ranging from about 0.1 to about 100,from about 0.5 to about 50, from about 1 to about 20 mg per day. Incertain embodiments, a method provided herein comprises administering tothe subject betahistine in the amount ranging from about 0.1 to about100 mg per day. In certain embodiments, a method provided hereincomprises administering to the subject betahistine in the amount rangingfrom about 0.5 to about 50 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject betahistine inthe amount ranging from about 1 to about 20 mg per day. In certainembodiments, a method provided herein comprises administering to thesubject betahistine in the amount of about 1, about 2, about 3, about 4,about 5, about 6, about 8, about 10, about 12, about 14, about 16, about18, or about 20 mg per day.

In certain embodiments, betahistine in a method provided herein isadministered once daily (QD) or divided into multiple daily doses suchas twice daily (BID), three times daily (TID), four times daily (QID),five times daily, or six times daily. In certain embodiments,betahistine in a method provided herein is administered QD. In certainembodiments, betahistine in a method provided herein is administeredBID. In certain embodiments, betahistine in a method provided herein isadministered TID. In certain embodiments, betahistine in a methodprovided herein is administered QID.

In certain embodiments, betahistine in a method provided herein isadministered concurrently or sequentially in any order with thephosphodiesterase inhibitor, adenosine receptor antagonist, calciumchannel blocker, and/or β₂-adrenoreceptor agonist. In certainembodiments, betahistine in a method provided herein is administeredconcurrently with the β₂-adrenoreceptor agonist. In certain embodiments,the dihydropyridine in a method provided herein is administeredconcurrently with the β₂-adrenoreceptor agonist in a singlepharmaceutical composition provided herein. In certain embodiments,betahistine in a method provided herein is administered concurrentlywith the phosphodiesterase inhibitor, adenosine receptor antagonist,calcium channel blocker, and/or β₂-adrenoreceptor agonist. In certainembodiments, the dihydropyridine in a method provided herein isadministered concurrently with the phosphodiesterase inhibitor,adenosine receptor antagonist, calcium channel blocker, and/orβ₂-adrenoreceptor agonist in a single pharmaceutical compositionprovided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)optionally one or more compounds, wherein each compound is independentlya calcium channel blocker or a β₂-adrenergic receptor agonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) a xanthine compound or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) betahistine, a metabolite thereof, or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a calcium channel blocker or a β₂-adrenergicreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a calcium channel blocker. In another embodiment, a method providedherein comprises administering to the subject: (i) a xanthine compoundor an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) betahistine, a metabolite thereof, oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) a β₂-adrenergic receptor agonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) two compounds, wherein each compound isindependently a calcium channel blocker or a β₂-adrenergic receptoragonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii) acalcium channel blocker; and (iv) a β₂-adrenergic receptor agonist.

In certain embodiments, the weight ratio of the xanthine compound tobetahistine in a method provided herein is ranging from about 2 to about200, from about 4 to about 100, from about 5 to about 50, or from about10 to about 30. In certain embodiments, the weight ratio of the xanthinecompound to betahistine in a method provided herein is about 10, about12, about 14, about 16, about 17, about 18, about 19, about 20, about21, about 22, about 23, about 24, about 25, about 26, about 27, about28, about 29, or about 30.

In certain embodiments, betahistine in a method provided herein isadministered concurrently or sequentially in any order with the xanthinecompound, calcium channel blocker, or β₂-adrenoreceptor agonist. Incertain embodiments, betahistine in a method provided herein isadministered concurrently with the xanthine compound, calcium channelblocker, and β₂-adrenoreceptor agonist. In certain embodiments, thedihydropyridine in a method provided herein is administered concurrentlywith the xanthine compound, calcium channel blocker, andβ₂-adrenoreceptor agonist in a single pharmaceutical compositionprovided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)optionally one or more compounds, wherein each compound is independentlya phosphodiesterase inhibitor, an adenosine receptor antagonist, or aβ₂-adrenoreceptor agonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) a dihydropyridine or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; and(ii) betahistine, a metabolite thereof, or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a phosphodiesterase inhibitor, an adenosinereceptor antagonist, and a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a phosphodiesterase inhibitor or an adenosine receptor antagonist. Inanother embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a β₂-adrenoreceptor agonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) two compounds, wherein each compound isindependently a phosphodiesterase inhibitor, an adenosine receptorantagonist, or a β₂-adrenoreceptor agonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii) aphosphodiesterase inhibitor or an adenosine receptor antagonist; and(iv) a β₂-adrenoreceptor agonist.

In certain embodiments, the weight ratio of the dihydropyridine tobetahistine in a method provided herein is ranging from about 1 to about50, from about 1 to about 40, from about 1 to about 20, or from about 1to about 10. In certain embodiments, the weight ratio of thedihydropyridine to betahistine in a method provided herein is about 1,about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5,about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8,about 8.5, about 9, about 9.5, or about 10.

In certain embodiments, betahistine in a method provided herein isadministered concurrently or sequentially in any order with thephosphodiesterase inhibitor, adenosine receptor antagonist,dihydropyridine, or β₂-adrenoreceptor agonist. In certain embodiments,betahistine in a method provided herein is administered concurrentlywith the phosphodiesterase inhibitor, adenosine receptor antagonist,dihydropyridine, and β₂-adrenoreceptor agonist. In certain embodiments,the dihydropyridine in a method provided herein is administeredconcurrently with the phosphodiesterase inhibitor, adenosine receptorantagonist, dihydropyridine, and β₂-adrenoreceptor agonist in a singlepharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (iii) betahistine, ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iv)optionally a β₂-adrenoreceptor agonist.

In certain embodiments, betahistine in a method provided herein isadministered concurrently or sequentially in any order with the xanthinecompound, dihydropyridine, or β₂-adrenoreceptor agonist. In certainembodiments, betahistine in a method provided herein is administeredconcurrently with the xanthine compound, dihydropyridine, andβ₂-adrenoreceptor agonist. In certain embodiments, the dihydropyridinein a method provided herein is administered concurrently with thexanthine compound, dihydropyridine, and β₂-adrenoreceptor agonist in asingle pharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) albuterol, or an enantiomer, a mixture of enantiomers;or levalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) one or morecompounds, wherein each compound is independently a PDE inhibitor, anadenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)a PDE inhibitor, an adenosine receptor antagonist, a calcium channelblocker, a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) albuterol, or an enantiomer, a mixture of enantiomers;or levalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) a PDE inhibitoror an adenosine receptor antagonist. In another embodiment, a methodprovided herein comprises administering to the subject: (i) albuterol,or an enantiomer, a mixture of enantiomers; or levalbuterol; or anisotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (ii) a calcium channel blocker. In yetanother embodiment, a method provided herein comprises administering tothe subject: (i) albuterol, or an enantiomer, a mixture of enantiomers;or levalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; and (ii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) albuterol, or an enantiomer, a mixtureof enantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)two compounds, wherein each compound is independently a PDE inhibitor,an adenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) albuterol, or an enantiomer, a mixture of enantiomers;or levalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a PDE inhibitor oradenosine receptor antagonist; and (iii) a calcium channel blocker. Inanother embodiment, a method provided herein comprises administering tothe subject: (i) albuterol, or an enantiomer, a mixture of enantiomers;or levalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a PDE inhibitor oradenosine receptor antagonist; and (iii) a histamine H₁-receptoragonist, a histamine H₂-receptor agonist, or a histamine H₃-receptorantagonist. In yet another embodiment, a method provided hereincomprises administering to the subject: (i) albuterol, or an enantiomer,a mixture of enantiomers; or levalbuterol; or an isotopic variantthereof; or a pharmaceutically acceptable salt, hydrate, or solvatethereof; (ii) a calcium channel blocker; and (iii) a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) albuterol, or an enantiomer, a mixtureof enantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (ii)three compounds, wherein each compound is independently a PDE inhibitor,an adenosine receptor antagonist, a calcium channel blocker, a histamineH₁-receptor agonist, a histamine H₂-receptor agonist, or a histamineH₃-receptor antagonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) albuterol, or an enantiomer, a mixture of enantiomers;or levalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) a PDE inhibitor or anadenosine receptor antagonist; (iii) a calcium channel blocker; and (iv)a histamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In certain embodiments, the weight ratio of (i) the phosphodiesteraseinhibitor or adenosine receptor antagonist to (ii) albuterol orlevalbuterol in a method provided herein is ranging from about 1 toabout 1,000, from about 10 to about 500, from about 20 to about 200, orfrom about 50 to about 200. In certain embodiments, the weight ratio of(i) the phosphodiesterase inhibitor or adenosine receptor antagonist to(ii) albuterol or levalbuterol in a method provided herein is about 50,about 60, about 70, about 80, about 90, about 100, about 110, about 120,about 130, about 140, about 150, about 160, about 170, about 180, about190, or about 200.

In certain embodiments, the weight ratio of (i) the calcium channelblocker to (ii) albuterol or levalbuterol in a method provided herein isranging from about 1 to about 100, from about 5 to about 50, or fromabout 5 to about 20. In certain embodiments, the weight ratio of (i) thecalcium channel blocker to (ii) albuterol or levalbuterol in a methodprovided herein is about 5, about 6, about 7, about 8, about 9, about10, about 11, about 12, about 13, about 14, about 15, about 16, about16, about 17, about 18, about 19, or about 20.

In certain embodiments, the weight ratio of (i) the histamineH₁-receptor agonist, histamine H₂-receptor agonist, or histamineH₃-receptor antagonist to (ii) albuterol or levalbuterol in a methodprovided herein is ranging from about 1 to about 100, from about 1 toabout 50, from about 1 to about 30, or from about 1 to about 20. Incertain embodiments, the weight ratio of (i) the histamine H₁-receptoragonist, histamine H₂-receptor agonist, histamine H₃-receptor antagonistto (ii) albuterol or levalbuterol in a method provided herein is about1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about9, about 10, about 11, about 12, about 13, about 14, about 15, about 16,about 17, about 18, about 19, or about 20.

In certain embodiments, a method provided herein comprises administeringto the subject albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof in a subtherapeuticallyeffective amount. In certain embodiments, a method provided hereincomprises administering to the subject albuterol or levalbuterol(micronized or non-micronized) in the amount ranging from about 0.1 toabout 50, from about 0.2 to about 20, or from about 0.5 to about 10 mgper day. In certain embodiments, a method provided herein comprisesadministering to the subject albuterol or levalbuterol in the amountranging from about 0.1 to about 50 mg per day. In certain embodiments, amethod provided herein comprises administering to the subject albuterolor levalbuterol in the amount ranging from about 0.2 to about 20 mg perday. In certain embodiments, a method provided herein comprisesadministering to the subject albuterol or levalbuterol in the amountranging from about 0.5 to about 10 mg per day. In certain embodiments, amethod provided herein comprises administering to the subject albuterolor levalbuterol in the amount of about 0.1, about 0.2, about 0.5, about1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about4.5, about 5, about 6, about 7, about 8, about 9, or about 10 mg perday.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered once daily (QD) or divided into multiple dailydoses such as twice daily (BID), three times daily (TID), four timesdaily (QID), five times daily, or six times daily. In certainembodiments, albuterol or levalbuterol in a method provided herein isadministered QD. In certain embodiments, albuterol or levalbuterol in amethod provided herein is administered BID. In certain embodiments,albuterol or levalbuterol in a method provided herein is administeredTID. In certain embodiments, albuterol or levalbuterol in a methodprovided herein is administered QID.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe phosphodiesterase inhibitor, adenosine receptor antagonist, calciumchannel blocker, histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist. In certain embodiments,albuterol or levalbuterol in a method provided herein is administeredcurrently with the histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist. In certain embodiments,albuterol or levalbuterol in a method provided herein is administeredcurrently with the histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist in a single pharmaceuticalcomposition provided herein. In certain embodiments, albuterol orlevalbuterol in a method provided herein is administered currently withthe phosphodiesterase inhibitor, adenosine receptor antagonist, calciumchannel blocker, histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist. In certain embodiments,albuterol or levalbuterol in a method provided herein is administeredcurrently with the phosphodiesterase inhibitor, adenosine receptorantagonist, calcium channel blocker, histamine H₁-receptor agonist,histamine H₂-receptor agonist, or histamine H₃-receptor antagonist in asingle pharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) optionally one or more compounds,wherein each compound is independently a calcium channel blocker, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) a xanthine compound or an isotopic variant thereof;or a pharmaceutically acceptable salt, hydrate, or solvate thereof and(ii) albuterol, or an enantiomer, a mixture of enantiomers; orlevalbuterol; or an isotopic variant thereof or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a calcium channel blocker, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) a calcium channel blocker. Inanother embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) a xanthine compound or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)two compounds, wherein each compound is independently a calcium channelblocker, a histamine H₁-receptor agonist, a histamine H₂-receptoragonist, or a histamine H₃-receptor antagonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (iii) a calcium channel blocker; and (iv) ahistamine H₁- and/or H₂-receptor agonist, and/or a histamine H₃-receptorantagonist.

In certain embodiments, the weight ratio of (i) the xanthine compound to(ii) albuterol or levalbuterol in a method provided herein is rangingfrom about 1 to about 1,000, from about 10 to about 500, from about 20to about 400, or from about 40 to about 300. In certain embodiments, theweight ratio of (i) the xanthine compound to (ii) albuterol orlevalbuterol in a method provided herein is about 40, about 60, about80, about 100, about 120, about 140, about 160, about 180, about 200,about 220, about 240, about 260, about 280, or about 300.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe xanthine compound, calcium channel blocker, histamine H₁-receptoragonist, histamine H₂-receptor agonist, or histamine H₃-receptorantagonist. In certain embodiments, albuterol or levalbuterol in amethod provided herein is administered currently with the xanthinecompound, calcium channel blocker, histamine H₁-receptor agonist,histamine H₂-receptor agonist, or histamine H₃-receptor antagonist. Incertain embodiments, albuterol or levalbuterol in a method providedherein is administered currently with the xanthine compound, calciumchannel blocker, histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist in a single pharmaceuticalcomposition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) optionally one or more compounds,wherein each compound is independently a phosphodiesterase inhibitor, anadenosine receptor antagonist, a histamine H₁-receptor agonist,histamine H₂-receptor agonist, or histamine H₃-receptor antagonist.

In another embodiment, a method provided herein comprises administeringto the subject: (i) a dihydropyridine or an isotopic variant thereof ora pharmaceutically acceptable salt, hydrate, or solvate thereof and (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) a dihydropyridine or an isotopicvariant thereof or a pharmaceutically acceptable salt, hydrate, orsolvate thereof (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a phosphodiesterase inhibitor, an adenosine receptor antagonist, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iii) a phosphodiesterase inhibitor oran adenosine receptor antagonist. In another embodiment, a methodprovided herein comprises administering to the subject: (i) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (ii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iii) a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) a dihydropyridine or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)two compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (iii) a phosphodiesterase inhibitor or anadenosine receptor antagonist; and (iv) a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.

In certain embodiments, the weight ratio of (i) the dihydropyridine to(ii) albuterol or levalbuterol in a method provided herein is rangingfrom about 1 to about 100, from about 5 to about 50, or from about 10 toabout 20. In certain embodiments, the weight ratio of (i) thedihydropyridine to (ii) albuterol or levalbuterol in a method providedherein is about 1, about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 11, about 12, about 13, about 14,about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe phosphodiesterase inhibitor, adenosine receptor antagonist,dihydropyridine, histamine H₁-receptor agonist, histamine H₂-receptoragonist, or histamine H₃-receptor antagonist. In certain embodiments,albuterol or levalbuterol in a method provided herein is administeredcurrently with the phosphodiesterase inhibitor, adenosine receptorantagonist, dihydropyridine, histamine H₁-receptor agonist, histamineH₂-receptor agonist, or histamine H₃-receptor antagonist. In certainembodiments, albuterol or levalbuterol in a method provided herein isadministered currently with the phosphodiesterase inhibitor, adenosinereceptor antagonist, dihydropyridine, histamine H₁-receptor agonist,histamine H₂-receptor agonist, or histamine H₃-receptor antagonist in asingle pharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)optionally one or more compounds, wherein each compound is independentlya phosphodiesterase inhibitor, an adenosine receptor antagonist, or acalcium channel blocker.

In another embodiment, a method provided herein comprises administeringto the subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof.

In yet another embodiment, a method provided herein comprisesadministering to the subject: (i) betahistine, a metabolite thereof, oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) albuterol, or an enantiomer, a mixtureof enantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a phosphodiesterase inhibitor, an adenosine receptor antagonist, or acalcium channel blocker.

In one embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a phosphodiesterase inhibitor or an adenosine receptor antagonist. Inanother embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)a calcium channel blocker.

In still another embodiment, a method provided herein comprisesadministering to the subject: (i) betahistine, a metabolite thereof, oran isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; (ii) albuterol, or an enantiomer, a mixtureof enantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; and (iii)two compounds, wherein each compound is independently aphosphodiesterase inhibitor, an adenosine receptor antagonist, or acalcium channel blocker.

In one embodiment, a method provided herein comprises administering tothe subject: (i) betahistine, a metabolite thereof, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; (ii) albuterol, or an enantiomer, a mixture ofenantiomers; or levalbuterol; or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii) aphosphodiesterase inhibitor or an adenosine receptor antagonist; and(iv) a calcium channel blocker.

In certain embodiments, the weight ratio of (i) betahistine to (ii)albuterol or levalbuterol in a method provided herein is ranging fromabout 1 to about 100, from about 1 to about 50, from about 1 to about20, or from about 1 to about 10. In certain embodiments, the weightratio of (i) betahistine to (ii) albuterol or levalbuterol in a methodprovided herein is about 1, about 2, about 3, about 4, about 5, about 6,about 7, about 8, about 9, or about 10.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe phosphodiesterase inhibitor, adenosine receptor antagonist; calciumchannel blocker, or betahistine. In certain embodiments, albuterol orlevalbuterol in a method provided herein is administered currently withbetahistine. In certain embodiments, albuterol or levalbuterol in amethod provided herein is administered currently with betahistine in asingle pharmaceutical composition provided herein. In certainembodiments, albuterol or levalbuterol in a method provided herein isadministered currently with the phosphodiesterase inhibitor, adenosinereceptor antagonist; calcium channel blocker, and betahistine. Incertain embodiments, albuterol or levalbuterol in a method providedherein is administered currently with the phosphodiesterase inhibitor,adenosine receptor antagonist; calcium channel blocker, and betahistinein a single pharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii) adihydropyridine or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (iii) albuterol, or anenantiomer, a mixture of enantiomers; or levalbuterol; or an isotopicvariant thereof; or a pharmaceutically acceptable salt, hydrate, orsolvate thereof; and (iv) optionally a histamine H₁- and/or H₂-receptoragonist, and/or a histamine H₃-receptor antagonist.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe xanthine compound, dihydropyridine, a histamine H₁-receptor agonist,a histamine H₂-receptor agonist, or a histamine H₃-receptor antagonist.In certain embodiments, albuterol or levalbuterol in a method providedherein is administered currently with the xanthine compound,dihydropyridine, a histamine H₁-receptor agonist, a histamineH₂-receptor agonist, or a histamine H₃-receptor antagonist. In certainembodiments, albuterol or levalbuterol in a method provided herein isadministered currently with the xanthine compound, dihydropyridine, ahistamine H₁-receptor agonist, a histamine H₂-receptor agonist, or ahistamine H₃-receptor antagonist in a single pharmaceutical compositionprovided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof; ora pharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof; or a pharmaceutically acceptable salt,hydrate, or solvate thereof; and (iv) optionally a calcium channelblocker.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe xanthine compound, calcium channel blocker, or betahistine. Incertain embodiments, albuterol or levalbuterol in a method providedherein is administered currently with the xanthine compound, calciumchannel blocker, and betahistine. In certain embodiments, albuterol orlevalbuterol in a method provided herein is administered currently withthe xanthine compound, calcium channel blocker, and betahistine in asingle pharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a dihydropyridine or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (ii)betahistine, a metabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof; (iii)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof and (iv) optionally a PDE inhibitor or anadenosine receptor antagonist.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe PDE inhibitor, adenosine receptor antagonist, dihydropyridine, orbetahistine. In certain embodiments, albuterol or levalbuterol in amethod provided herein is administered currently with the PDE inhibitor,adenosine receptor antagonist, dihydropyridine, and betahistine. Incertain embodiments, albuterol or levalbuterol in a method providedherein is administered currently with the PDE inhibitor, adenosinereceptor antagonist, dihydropyridine, and betahistine in a singlepharmaceutical composition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject: (i) a xanthine compound or an isotopic variant thereof or apharmaceutically acceptable salt, hydrate, or solvate thereof (ii) adihydropyridine or an isotopic variant thereof or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof; (iii) betahistine, ametabolite thereof, or an isotopic variant thereof; or apharmaceutically acceptable salt, hydrate, or solvate thereof and (iv)albuterol, or an enantiomer, a mixture of enantiomers; or levalbuterol;or an isotopic variant thereof or a pharmaceutically acceptable salt,hydrate, or solvate thereof.

In certain embodiments, albuterol or levalbuterol in a method providedherein is administered concurrently or sequentially in any order withthe xanthine compound, dihydropyridine, or betahistine. In certainembodiments, albuterol or levalbuterol in a method provided herein isadministered currently with the xanthine compound, dihydropyridine, andbetahistine. In certain embodiments, albuterol or levalbuterol in amethod provided herein is administered currently with the xanthinecompound, dihydropyridine, and betahistine in a single pharmaceuticalcomposition provided herein.

In one embodiment, a method provided herein comprises administering tothe subject aminophylline or theophylline. In another embodiment, amethod provided herein comprises administering to the subjectnifedipine. In yet another embodiment, a method provided hereincomprises administering to the subject betahistine or betahistinehydrochloride. In still another embodiment, a method provided hereincomprises administering to the subject albuterol, albuterolhydrochloride, levalbuterol, or levalbuterol hydrochloride.

In one embodiment, a method provided herein comprises administering tothe subject (i) aminophylline or theophylline and (ii) nifedipine. Inanother embodiment, a method provided herein comprises administering tothe subject (i) aminophylline or theophylline and (ii) betahistine orbetahistine hydrochloride. In yet another embodiment, a method providedherein comprises administering to the subject (i) aminophylline ortheophylline and (ii) albuterol, albuterol hydrochloride, levalbuterol,or levalbuterol hydrochloride. In yet another embodiment, a methodprovided herein comprises administering to the subject (i) nifedipineand (ii) betahistine or betahistine hydrochloride. In yet anotherembodiment, a method provided herein comprises administering to thesubject (i) nifedipine and (ii) albuterol, albuterol hydrochloride,levalbuterol, or levalbuterol hydrochloride. In still anotherembodiment, a method provided herein comprises administering to thesubject (i) betahistine or betahistine hydrochloride; and (ii)albuterol, albuterol hydrochloride, levalbuterol, or levalbuterolhydrochloride.

In one embodiment, a method provided herein comprises administering tothe subject (i) aminophylline or theophylline; (ii) nifedipine; and(iii) betahistine or betahistine hydrochloride. In another embodiment, amethod provided herein comprises administering to the subject (i)aminophylline or theophylline; (ii) nifedipine; and (iii) albuterol,albuterol hydrochloride, levalbuterol, or levalbuterol hydrochloride. Inyet another embodiment, a method provided herein comprises administeringto the subject (i) aminophylline or theophylline; (ii) betahistine orbetahistine hydrochloride; and (iii) albuterol, albuterol hydrochloride,levalbuterol, or levalbuterol hydrochloride.

In one embodiment, a method provided herein comprises administering tothe subject (i) aminophylline or theophylline; (ii) nifedipine; (iii)betahistine or betahistine hydrochloride; and (iv) albuterol, albuterolhydrochloride, levalbuterol, or levalbuterol hydrochloride.

In certain embodiments, the weight ratio of theophylline to nifedipinein a method provided herein is ranging from about 1 to about 180, fromabout 2 to about 100, from about 2 to about 50, or from about 2 to about20. In certain embodiments, the weight ratio of theophylline tonifedipine in a method provided herein is ranging from about 1 to about180. In certain embodiments, the weight ratio of theophylline tonifedipine in a method provided herein is ranging from about 2 to about100. In certain embodiments, the weight ratio of theophylline tonifedipine in a method provided herein is ranging from about 2 to about50. In certain embodiments, the weight ratio of theophylline tonifedipine in a method provided herein is ranging from about 2 to about20. In certain embodiments, the weight ratio of theophylline tonifedipine in a method provided herein is about 2, about 4, about 6,about 8, about 10, about 12, about 14, about 16, about 18, or about 20.

In certain embodiments, the weight ratio of theophylline to betahistinein a method provided herein is ranging from about 2 to about 200, fromabout 4 to about 100, from about 5 to about 50, or from about 10 toabout 30. In certain embodiments, the weight ratio of theophylline tobetahistine in a method provided herein is about 10, about 12, about 14,about 16, about 18, about 20, about 22, about 24, about 26, about 28, orabout 30.

In certain embodiments, the weight ratio of theophylline to albuterol orlevalbuterol in a method provided herein is ranging from about 1 toabout 1,000, from about 10 to about 500, from about 20 to about 400, orfrom about 40 to about 300. In certain embodiments, the weight ratio oftheophylline to albuterol or levalbuterol in a method provided herein isabout 40, about 60, about 80, about 100, about 120, about 140, about160, about 180, about 200, about 220, about 240, about 260, about 280,or about 300.

In certain embodiments, the weight ratio of nifedipine to betahistine ina method provided herein is ranging from about 1 to about 50, from about1 to about 40, from about 1 to about 20, or from about 1 to about 10. Incertain embodiments, the weight ratio of nifedipine to betahistine in amethod provided herein is about 1, about 1.5, about 2, about 2.5, about3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, orabout 10.

In certain embodiments, the weight ratio of nifedipine to albuterol orlevalbuterol in a method provided herein is ranging from about 1 toabout 100, from about 5 to about 50, or from about 5 to about 20. Incertain embodiments, the weight ratio of nifedipine to albuterol orlevalbuterol in a method provided herein is about 5, about 6, about 7,about 8, about 9, about 10, about 11, about 12, about 13, about 14,about 15, about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, the weight ratio of betahistine to albuterol orlevalbuterol in a method provided herein is ranging from about 1 toabout 100, from about 1 to about 50, from about 1 to about 30, or fromabout 1 to about 20. In certain embodiments, the weight ratio ofbetahistine to albuterol or levalbuterol in a method provided herein isabout 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8,about 9, about 10, about 11, about 12, about 13, about 14, about 15,about 16, about 17, about 18, about 19, or about 20.

In certain embodiments, a method provided herein comprises administeringto the subject aminophylline in a subtherapeutically effective amount.In certain embodiments, a method provided herein comprises administeringto the subject aminophylline (micronized or non-micronized) in theamount ranging from about 1 to about 1,200 mg/day, from about to about1,000 mg/day, from about 1 to about 800 mg/day, from about 1 to about700 mg/day, from about 1 to about 600 mg/day, from about 1 to about 500mg/day, from about 1 to about 400 mg/day, from about 1 to about 300mg/day, from about 1 to about 200 mg/day, from about 1 to about 100mg/day, from about 1 to about 90 mg/day, from about 1 to about 80mg/day, from about 1 to about 70 mg/day, from about 1 to about 60mg/day, from about 1 to about 50 mg/day, from about 1 to about 40mg/day, from about 1 to about 30 mg/day, from about 1 to about 20mg/day, or from about 1 to about 10 mg/day.

In certain embodiments, a method provided herein comprises administeringto the subject theophylline (micronized or non-micronized) in asubtherapeutic effective amount. In certain embodiments, a methodprovided herein comprises administering to the subject theophylline inthe amount ranging from about 1 to about 1,200, from about to about1,000, from about 5 to about 800, or from about 10 to about 600 mg perday. In certain embodiments, a method provided herein comprisesadministering to the subject theophylline in the amount ranging fromabout 1 to about 1,200 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject theophylline inthe amount ranging from about 1 to about 1,000 mg per day. In certainembodiments, a method provided herein comprises administering to thesubject theophylline in the amount ranging from about 5 to about 800 mgper day. In certain embodiments, a method provided herein comprisesadministering to the subject theophylline in the amount ranging fromabout 20 to about 600 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject theophylline inthe amount of about 20, about 50, about 75, about 100, about 125, about150, about 175, about 200, about 225, about 250, about 275, about 300,about 325, about 350, about 375, about 400, about 425, about 450, about475, about 500, about 525, about 550, about 575, or about 600 mg perday.

In certain embodiments, a method provided herein comprises administeringto the subject nifedipine (micronized or non-micronized) in asubtherapeutically effective amount. In certain embodiments, a methodprovided herein comprises administering to the subject nifedipine in asubtherapeutic effective amount. In certain embodiments, a methodprovided herein comprises administering to the subject nifedipine in theamount ranging from about 0.1 to about 200, from about 1 to about 100,or from about 2 to about 60 mg per day. In certain embodiments, a methodprovided herein comprises administering to the subject nifedipine in theamount ranging from about 0.1 to about 200 mg per day. In certainembodiments, a method provided herein comprises administering to thesubject nifedipine in the amount ranging from about 1 to about 100 mgper day. In certain embodiments, a method provided herein comprisesadministering to the subject nifedipine in the amount ranging from about2 to about 60 mg per day. In certain embodiments, a method providedherein comprises administering to the subject nifedipine in the amountof about 2, about 5, about 10, about 15, about 20, about 25, about 30,about 35, about 40, about 45, about 50, about 55, or about 60 mg perday.

In certain embodiments, a method provided herein comprises administeringto the subject (i) aminophylline or theophylline, (ii) nifedipine, (iii)betahistine, and (iv) albuterol or levalbuterol; wherein the amount ofaminophylline or theophylline is from about 1 to about 1000 mg/day, theamount of nifedipine is from about 0.1 to about 180 mg/day, the amountof betahistine is from about 1 to about 100 mg/day, and wherein theamount of albuterol or levalbuterol is from about 0.1 to about 32mg/day.

In certain embodiments, (i) aminophylline or theophylline, (ii)nifedipine and (iii) betahistine in a method provided herein areadministered concurrently or sequentially in any order. In certainembodiments, (i) aminophylline or theophylline, (ii) nifedipine, and(iii) betahistide in a method provided herein are administeredconcurrently. In certain embodiments, (i) aminophylline or theophylline,(ii) nifedipine, and (iii) betahistine in a method provided herein areadministered concurrently in a single pharmaceutical compositionprovided herein.

In certain embodiments, (i) aminophylline or theophylline, (ii)nifedipine and (iii) albuterol or levalbuterol in a method providedherein are administered concurrently or sequentially in any order. Incertain embodiments, (i) aminophylline or theophylline, (ii) nifedipine,and (iii) albuterol or levalbuterol in a method provided herein areadministered concurrently. In certain embodiments, (i) aminophylline ortheophylline, (ii) nifedipine, and (iii) albuterol or levalbuterol in amethod provided herein are administered concurrently in a singlepharmaceutical composition provided herein.

In certain embodiments, (i) aminophylline or theophylline, (ii)betahistine, and (iii) albuterol, albuterol hydrochloride, levalbuterol,or levalbuterol hydrochloride in a method provided herein areadministered concurrently or sequentially in any order. In certainembodiments, (i) aminophylline or theophylline, (ii) betahistine, and(iii) albuterol, albuterol hydrochloride, levalbuterol, or levalbuterolhydrochloride in a method provided herein are administered concurrently.In certain embodiments, (i) aminophylline or theophylline, (ii)betahistine, and (iii) albuterol, albuterol hydrochloride, levalbuterol,or levalbuterol hydrochloride in a method provided herein areadministered concurrently in a single pharmaceutical compositionprovided herein.

In certain embodiments, (i) aminophylline or theophylline, (ii)nifedipine, (iii) betahistine or betahistine hydrochloride, and (iv)albuterol, albuterol hydrochloride, levalbuterol, or levalbuterolhydrochloride in a method provided herein are administered concurrentlyor sequentially in any order. In certain embodiments, (i) aminophyllineor theophylline, (ii) nifedipine, (iii) betahistine or betahistinehydrochloride, and (iv) albuterol, albuterol hydrochloride,levalbuterol, or levalbuterol hydrochloride in a method provided hereinare administered concurrently. In certain embodiments, (i) aminophyllineor theophylline, (ii) nifedipine, (iii) betahistine or betahistinehydrochloride, and (iv) albuterol, albuterol hydrochloride,levalbuterol, or levalbuterol hydrochloride in a method provided hereinare administered concurrently in a single pharmaceutical compositionprovided herein.

In certain embodiments, a method provided herein comprises administeringto the subject a pharmaceutical composition provided herein. In certainembodiments, the pharmaceutical composition is administered once daily(QD), or divided into multiple daily doses such as twice daily (BID),three times daily (TID), four times daily (QID), five times daily, orsix times daily. In certain embodiments, the pharmaceutical compositionis administered QD. In certain embodiments, the pharmaceuticalcomposition is administered BID. In certain embodiments, thepharmaceutical composition is administered TID. In certain embodiments,the pharmaceutical composition is administered QID. In certainembodiments, the pharmaceutical composition is administered orally. Incertain embodiments, the pharmaceutical composition is administeredorally as a capsule.

In certain embodiments, a method provided herein comprises administeringto the subject each active compound before a meal. In certainembodiments, a method provided herein comprises administering to thesubject each active compound after a meal.

In certain embodiments, a method provided herein for treating cerebralvascular thrombosis comprises administering to the subject each activecompound at bedtime. In certain embodiments, a method provided hereinfor treating cerebral vascular thrombosis comprises administering to thesubject each active compound in the morning and at bedtime. In certainembodiments, a method provided herein for treating cerebral vascularthrombosis comprises administering to the subject each active compoundin the morning and midday and at bedtime. In certain embodiments, amethod provided herein for treating cerebral vascular thrombosiscomprises administering to the subject each active compound at about 6AM, 2 PM, and 10 PM. In certain embodiments, a method provided hereinfor treating cerebral vascular thrombosis comprises administering to thesubject each active compound in the morning at about 4 AM to 8 AM. Incertain embodiments, a method provided herein for treating cerebralvascular thrombosis comprises administering to the subject each activecompound in midday at noon to 4 PM. In certain embodiments, a methodprovided herein for treating cerebral vascular thrombosis comprisesadministering to the subject each active compound at bedtime at 8 PM tomidnight.

In certain embodiments, the subject is a mammal. In certain embodiments,the subject is a human.

The methods provided herein encompass treating a subject regardless ofpatient's age, although some diseases or disorders are more common incertain age groups. Depending on the disease to be treated and thesubject's condition, each active compound can independently beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, ICV, intracistemal injection or infusion, subcutaneousinjection, or implant), inhalation, nasal, vaginal, rectal, sublingual,or topical (e.g., transdermal or local) routes of administration and canbe formulated, alone or together, in suitable dosage unit withpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificactive compound employed, the metabolic stability and length of actionof that active compound, the age, body weight, general health, sex,diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

In certain embodiments, provided herein are kits which, when used by themedical practitioner, can simplify the administration of appropriateamounts of active ingredients to a subject. In certain embodiments, thekit provided herein includes a container and a dosage form of an activecompound provided herein or a pharmaceutical composition providedherein, in a container comprising one or more other therapeutic agent(s)described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, water for injectionUSP, sodium chloride injection, Ringer's injection, dextrose injection,dextrose and sodium chloride injection, and lactated Ringer's injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES Example 1

A Two-API Combination

When aminophylline (a phosphodiesterase inhibitor and adenosine receptorantagonist commonly used in the treatment of asthma) and clenbuterol (aβ₂ agonist useful in the treatment of asthma) were prescribed to treat apatient needing bronchodilation, it was observed that the 2-drugcombination, as undesired side effects for the prescribed treatment,increased the patient' heart rate significantly. The observation of theunwanted side effects led to the hypothesis that a combination ofaminophylline and clenbuterol might be useful in treating a bradycardiapatient. To test this hypothesis, an experiment was conducted, where acombination of aminophylline and clenbuterol was administered to a smallgroup of volunteer subjects. After about 2-3 hours, the subjects' heartrates increased by 5-6 beats per minute. The effect lasted about 6 to 8hours. For each subject in this example, an electrocardiogram (ECG) wasused to monitor heart rate and A-V conduction abnormalities.

Even though an increase of 5-6 beats per minute in heart rate observedin this example was not as large as an increase typically achieved witha pacemaker implantation, such an increase is significant, especiallywhen there is no approved drug even today for treating bradycardiapatients who either did not or could not receive a pacemaker. The drugcombination was tested on bradycardia patients, and the pateints treatedwith the 2-combination were observed to have a heart rate increase of5-6 beats per minute on average in this example.

Example 2

Three-API Combinations

To further improve the effect of the aminophylline and clenbuterolcombination on the heart rate, various combinations with activepharmaceutical ingredients were investigated. Without being bound bytheory, the hypothesis in this experiment was to utilize a combinationof APIs with similar mechanism of action or with the same side effect (asecondary therapeutical effects) on heart as aminophylline andclenbuterol. Oryzanol, nicotinamide, or anisodamine in combination withaminophylline and clenbuterol was tested on a small group of volunteersubjects. However, there was no further improvement observed.

Nifedipine (a calcium channel blocker) was then selected and tested.Although the primary indication of nifedipine is vasospastic angina andchronic stable angina, nifedipine combined with aminophylline andclenbuterol, when tested on a small group of volunteer subjects, led toenhanced effects on the heart rate compared to the results of Example 1.After two to three hours following administration of the 3-APIcombination, the subjects' heart rates increased by 7-9 beats perminute. The increased heart rate effect lasted about 6 to 8 hours. Thecombination of 3 APIs was then tested on patients with symptomatic sinusbradycardia. The bradycardia patients treated with the 3-drugcombination were observed to have a heart rate increase of 7-9 beats perminute on average.

Example 3

Four-API Combinations

During the treatment of a vertigo patient, it was observed that thepatient's heart rate was noticeably increased after administeringbetahistine. Although betahistine is commonly prescribed to patientswith balance disorders or to alleviate vertigo symptoms associated withMeniere's disease, it had not been used for treating bradycardia. Basedon this observation, betahistine was selected as one of potential APIsin combination for treating bradycardia. A combination of betahistinewith aminophylline, clenbuterol, and nifedipine was then prepared andtested on a small group of healthy volunteer subjects. The results fromthe healthy volunteer subjects showed an increase in heart rate of 10beats per minute or even higher. This 4-API combination was also testedon bradycardia patients. The results from the bradycardia patientsshowed a heart rate increase of 10 beats per minute or greater.

During the testing of the 4-API combination on bradycardia patients, afew adverse side effects were observed on some patients. These sideeffects included hand tremors and convulsions gastrocnemius. Therefore,a further study was conducted to determine how to avoid or reduce suchside effects. After careful investigation, it was found that these sideeffects were related to clenbuterol. To confirm this finding,clenbuterol was replaced by albuterol in the 4-API combination, whichhas a similar secondary therapeutical effect on heart rate. It was foundthat the side effects (hand tremors and convulsions gastrocnemius) wereeither significantly reduced or eliminated as a result of clenbuterolbeing substituted with albuterol. Daily electrocardiograms were used tomonitor the bradycardia patients. The patients treated with the new4-API combination showed a heart rate increase by 10 beats per minute orgreater. With this improvement, the effectiveness of the treatment onbradycardia patients was retained while the undesired side effects wereminimized or eliminated.

Additional modifications were made to improve the 4-API combinations:(I) aminophylline was replaced by theophylline as aminophylline causeddegradation of another API and affected the stability of a 4-APIcomposition formulation; (2) albuterol (50% R-albuterol and 50%S-albuterol) was replaced by equivalently active levalbuterol (purity100% R-albuterol) because (5)-albuterol is either inert or has someadverse effects; only (R)-albuterol is believe to have the desiredpharmacological activities; and (3) micronized theophylline andnifedipine were used to enhance their bioavailabilities.

Example 4

4-API Pharmaceutical Formulation

Pharmaceutical formulations comprising micronized theophylline (or anisotopic variant thereof) (API-1), micronized nifedipine (or an isotopicvariant thereof) (API-2), betahistine dihydrochloride (or an isotopicvariant thereof) (API-3), and levalbuterol hydrochloride (or an isotopicvariant thereof) (API-4) were prepared following the Current GoodManufacturing Practices (CGMPs). Levalbuterol hydrochloride (API-4) wasblended with 10 wt % of total microcrystalline cellulose for 5 min.Micronized nifedipine (API-2) and 20 wt % of total microcrystallinecellulose were added and the resulting mixture was blended for 5 min.Betahistine dihydrochloride (API-3) and 30 wt % of totalmicrocrystalline cellulose were added and the resulting mixture wasblended for 5 min. Micronized theophylline (API-1) and 40 wt % of totalmicrocrystalline cellulose were added and the resulting mixture wasblended for 5 min. Mannitol, sodium starch glycolate, colloidal silicondioxide, and citric acid were added, followed by addition of magnesiumstearate. The resulting mixture was blended for 5 min and formulatedinto capsules in a size of 000, 00, 0, 1, 2, 3, 4, or 5. Each micronizedAPI was prepared via jet milling.

TABLE 6 Patients Treated with 4-API Combinations Pre- Post- TreatmentTreatment Gender (Age) Cardiovascular Symptom Before Treatment (ECG, HR,etc.) HR (BPM) HR (BPM) Female (65) In 5 years, often feeling chesttightness, palpitations dizziness and 45-54 (day)  69(day)  seizureamaurosis fugax in recent two weeks, collapsed with sudden 28-46 (night)61(night) loss of consciousness during talking one hour ago and sent tohospital. Sinus rhythm ECG shows, daytime heart rate 45-54 BPM, at night28- 46 BPM, maximum R-R Spacing2.5 Second, V5 Lead ST Move down 0.8 mm,Diagnosis of coronary artery disease, sick sinus syndrome, adams-stokessyndrome. Treatment: daily intravenous hydrogenated to cortisone 200 mg;Oral taking ubidecarenone, aminophylline, atropine, and nicotinamide.Continuous administration for 7 Days, still have seizures amaurosisfugax attach, illness without obvious improvement Female (59) Because ofheart palpitations dizziness fatigue, Collapsed convulsions 36-37 54happened within a month and then hospitalized. Third-degree A-V block,ventricular rate 37 beats/minutes. Diagnosis of coronary heart disease,complete A-V block, adams-stokes syndrome. Treatment: daily intravenousinfusion isoprenaline; Oral atropine, aminophylline, nicotinamide, Aftercontinuous treatment for 10 days, ECG showed the ventricular rate was 36BPM. Patients couldn't get out of bed, and had coma twitch during thesedays. Doctors' consultation recommended the immediate placement ofpacemakers, but pacemaker was refused by the patient and her families.Male (43) Dizziness, memory loss and physical decline for over a year,the outer 25-45 61 Court Holter Report: two two-sinus block, sinusstationary, and escape, and the slowest heart rate 25 BPM, SNRT 4200 ms,diagnosed with SS syndrome, Used anisodamine, nicotinamide,dexamethasone, and taking Chinese medicine Xin Bao for a long time, theeffect is not obvious. Patient was unwilling to accept the pacemaker,and come from laiwu city, Shandong province to Beng hospital fortreatment. At time of receiving, ECG Report: HR 45 BPM. Male (67) Chesttightness, dizziness for more than a month, syncope for once. 32-45 63.Holter inspection report: junctional rhythm. The slowest HR 32 BPM. 24hours' average HR: 45, diagnosis with SS syndrome. There is no responseby treatment with atropine, and nicotinamide. Male (61) Dizzinessfatigue for more than one year. ECG Shows an A-V block, 38 45ventricular rate 38 BPM. 10 days' treatment with dexamethasone,nicotinamide, vitamin B₂, and atropine was ineffective. Male (59)Suddenly collapsed while working in the Office and patient was 41 71.hospitalized. ECG shown sinus rhythm, HR 41 BPM, esophageal pacing SNRT1860 ms, SACT430 ms, Diagnosed with SS syndrome. No obvious effect bytreatment with atropine, and nicotinamide. Because of dry mouth inpatients and dysuria, patient can't tolerate with atropine. Female (45)Sluggish chest tightness, palpitations for 3 years, getting worse for 3663 more than a month, and sometimes dizziness, occasional fainting. ECGshows sinus bradycardia and arrhythmia, HR 36 BPM, diagnosis with SSsyndrome. No effect by treatment with atropine, and/or some traditionalmedicine. Male (48) Because of dizziness, tightness in the chest andcould not stand. Patient 26-44 71 was hospitalized 3 hours later, ECGreport: sinus rhythm, HR was between 26 to 44 BPM. Diagnosed with SSsyndrome and acute myocarditis. There is no obvious effect aftertreatment with IV isoprenaline, or oral administration of atropine. Male(73) Tightness in the chest, swelling of lower extremities, bradycardiafor 2 41-51 71 years. ECG shown sinus rhythm, and HR was 51 BPM.Paroxysmal junctional escape rhythm HR was 41 BPM. Myocardial strain andsecond degree atrioventricular block. Diagnose as SS syndrome. There isno obvious effect after treatment with isosorbide, atropine, andnicotinamide. Male (63) Palpitation chest tightness, dizziness, lackingin strength for half a 41-50 68 month and was hospitalized. ECG showssinus bradycardia and arrhythmia, HR between 41 and 50 BPM, seconddegree type of sinus block, Junctional escape beat, diagnosed as SSsyndrome. There is no obvious effect after treatment with isosorbide,and nicotinamide. Female (41) Sluggish chest tightness, palpitations andlacking in strength for 3 36 73 years. Patient was hospitalized becauseof dizziness and passed out. ECG shows sinus bradycardia and HR 36 BPM,sinus arrest, and junctional escape. Holter reported RR interval ≥2seconds 13 times and maximum interval 2.6 seconds. Patient was diagnosedwith SS syndrome. There is no obvious effect after treatment withisosorbide, Nifedipine, nicotinamide, and atropine. Patient is stillsick in bed. Male (67) Fatigue and dizziness for 2 years. The patientwas diagnosed as 39 51 coronary heart disease by Heilongjiang provincialhospital. ECG shows an A-V block and the ventricular rate 39 BPM.Treatment with nitroglycerin, and nicotinamide is ineffective.Provincial hospital recommended placing cardiac pacemaker. Patient isunwilling to use the pacemaker. Female (51) Chest tightness, dizzinessand feeling fatigue for more than a year. The 28-35 56 Holter reportshowed the slowest HR 35 BPM, due to high grade A-V block. The slowestventricular rate was 28 BPM. There is no improvement after treatmentwith aminophylline, and nicotinamide. Doctors suggest using pacemaker.As a hospital director, the patient didn't want to use the pacemaker.Female (35) Dizziness and fatigue for more than two years. ECG shown HR35-50 61 between 35 to50 BPM. Patient was diagnosed as SS syndrome by aHospital of Cardiology. There is no improvement after treatment withatropine and nicotinamide. The pacemaker was suggested to patients butwas refused. Female (53) Dizziness and fatigue for more than two years.ECG shown HR 44-48 63. between 44 and 48 BPM, arrhythmias, and frequentatrial premature beats. There is no obvious effect after treatment withoxyfedrine, prednisone, and nicotinamide, etc. The patient felt noimprovement. Male (52) Dizziness and weakness. Slow HR for 5 years.Ineffective treatment in 39 63 a few hospitals. Patient was diagnosed asSS syndrome by a hospital. ECG shown HR 39 BPM. Doctor recommendspacemaker but was refused by the patient. Female (42) Palpitation chesttightness, dizziness and fatigue for more than 3 years. 39-49 64 TheHolter examination results: During 24 hours, the fastest HR 49 BPM, andthe slowest HR 39 BPM, the longest RR interval was 2.6 seconds,diagnosed as SS syndrome. There is no obvious effect after treatmentwith atropine, nicotinamide, dexamethasone, intravenous injection offructose diphosphate. When the patient came to the hospital, ECG shownHR41 BPM. Female (29) Palpitation, shortness of breath, and fatigue for5 years. ECG shown an 39-41 54. A-V block and the ventricular rate 41BPM. There is no obvious effect after treatment with atropine,dexamethasone, and energy agents. Hospital recommended a pacemaker butthe patient refused. When the patient arrived the hospital, ECG shown anA-V block and HR was 39 BPM. Female (25) Palpitation and shortness ofbreath for 2 years. Holter examination 33-34 47 shown an A-V block. Theventricular rate was 34 BPM. The hospital suggested that the drugtreatment won't have the effect in this case and recommended the use ofpacemaker. Patients was unwilling to place a pacemaker. When the patientarrived our hospital, ECG shown ventricular rate was 33 BPM. Male (58)Palpitation, shortness of breath, and fatigue for 5 years. The hospital31-38 58 diagnosed as rheumatic heart disease, mitral insufficiency,left atrial and right ventricular enlargement. Holter examinationreport: atrial fibrillation, A-V block, the slowest ventricular rate31BPM, the fastest 48 BPM, average41 BPM. Recommended placement ofpacemakers but refused by the patient. When the patient arrived ourhospital, ECG shown atrial fibrillation and ventricular rate 38 BPM.

Example 5

Quality Control

Several analytical methods for identification and quantitation of theAPIs in the pharmaceutical compositions prepared were developed andfully validated following the US and global standards. One assay methodwas developed for identification and quantitation of API-1 and API-2 byHPLC. Another assay method was developed for identification andquantitation of API-3 and API-4 by HPLC. The United States Pharmacopeial(USP) grade reference standards of APIs were used to quantify theconcentrations of the APIs in the pharmaceutical compositions.

A Distek 5100 Dissolution Apparatus was used in a dissolution assay forAPI-1 and API-2. A Hanson Sr8-Plus Dissolution Apparatus was used in adissolution assay for API-3 and API-4.

Several batches of the pharmaceutical compositions were prepared. Thestability studies of the pharmaceutical compositions were conductedfollowing the US and International Council for Harmonisation (ICH)Guidelines. The stability samples were stored under the followingconditions: (1) preferred conditions: 25° C.±2° C., 60%±5% relativehumidity (RH); (2) accelerated conditions: 40° C.±2° C., 75%±5% RH; or(3) intermediate conditions: 30° C.±2° C., 65%±5% RH. Stability studieswere completed with a 6-month under the accelerated condition attemperature of 40° C./75% RH, and an 18-month under the preferredconditions at temperature of 25° C./60% RH. The pharmaceuticalcompositions were stable for more than 2-years, and thus met therequirements of the US and ICH guidelines.

Example 6

Cardiovascular Evaluation of 4-API Composition in Animals

A cardiovascular evaluation of an orally administered 4-API compositionin beagle dogs was carried out. Five male experimental non-naïve beagledogs, approximately 1 year and 8 months to 1 year and 11 months of age,were selected. All animals were given a physical examination prior toselection for study. The animals were weighed periodically and observedwith respect to general health and any signs of a disease. Baselinecardiovascular telemetry monitoring (body temperature, blood pressure,heart rate, and the electrocardiogram) was conducted.Electrocardiographic (ECG) tracings from the 24-hour baselinecardiovascular monitoring sessions were evaluated for all animals torule out electrophysiological abnormalities of the heart and todetermine suitability for the study. All animals had blood samplescollected pretest to evaluate clinical chemistry and hematologyparameters. All animals selected for study were considered suitablebased on pretest evaluations.

No relevant abnormal clinical signs were noted following administrationof a 4-API composition of Table 1. The clinical observations includedbody weights, body temperature, systolic, diastolic and mean arterialblood pressures, heart rate, RR interval, PR interval, WRS duration, QTinterval and corrected QT interval, and electrocardiography.

Acute oral administration of the 4-API composition in dogs at test doseswas without mortality and did not produce clinical signs or effects onbody temperature, QTc, or the qualitative aspects of the ECG.

The 4-API composition at the test doses produced non-dose dependentdecreases in blood pressure and slight increases in QRS duration.Dose-dependent increases in heart rate were observed at all dose levels,which resulted in rate-related changes in the quantitative ECGparameters (RR, PR, QT).

Example 7

Dosage Forms of 4-API Compositions

Several dosage forms were prepared as shown in Table 2. The low dose isdesigned to treat patients with early stage bradycardia; the middle doseis designed to treat symptomatic sinus patients; and the high dose isdesigned to treat severe symptomatic sinus patients or Atrio-Ventricularblock patients.

TABLE 1 Phamaceutical Compositions Composition Weight (%) Theophylline(or an isotopic 1-20, 1-30, 2-35, 2-40, 2-45, 2-50, 2-55, variantthereof) (API-1) 3-60, 3-65, 4-70, 4-75, 5-80, 5-85, or 5-90% Nifedipine(or an isotopic 0.1-2, 0.1-3, 0.2-4, 0.2-5, 0.4-6, 0.4-6.5, variantthereof) (API-2) 0.5-7, 0.5-7.5, 1-8, 1-8.5, 1-9, 1-9.5, or 1-10%Betahistine (or an isotopic 0.02-1, 0.02-2, 0.02-3, 0.02-4, 0.2-5,variant thereof) (HCl)₂ 0.2-6, 0.2-7, 0.5-8, 0.5-9, 1-9.5, or 1-10%(API-3) Levalbuterol HCl (or an 0.002-0.5, 0.002-1, 0.002-1.5, 0.02-2,isotopic variant thereof) 0.02-2.5, 0.02-3, 0.02-3.5, 0.2-4, 0.2-4.5,(API-4) or 0.2-5% Microcrystalline cellulose 2-5%, 2-10%, 5-15%, 5-20%,5-25%, 5-30%, 5-35%, 5-40%, 10-45%, 10-50%, 10-55%, 10-60%, or 10-65%Mannitol 2-5%, 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 5-35%, 5-40%, 10-45%,10-50%, 10-55%, 10-60%, or 10-65% Sodium starch glycolate 1-2%, 1-3%,1-4%, or 1-5% Colloidal silicon dioxide 0.02-0.05, 0.02-0.1%,0.02-0.15%, or 0.02-0.2% Magnesium stearate 0.05-0.1%, 0.05-0.15%,0.1-0.2% 0.1-0.3%, 0.1-0.4%, or 0.1-0.5% Citric acid 0.1-0.2%, 0.1-0.4%,0.1-0.6, 0.1-0.8%, or 0.1-1%

Example 8

Cardiovascular Evaluation of 4-API Compositions in Healthy Volunteers

To evaluate the cardiovascular effects of the 4-API compositionsdescribed in Example 7 above, two healthy volunteer subjects wereparticipated. To obtain heart rate (HR) base lines, the two volunteersubjects were measured for heart rates, without any medication, daily at7:00, 10:00, and 18:00 in a sitting position, quiet and resting for 10minutes before each measurement, recording HR once per each time point(3 time points per day) for 3 consecutive days.

The average of all measurements was calculated as a baseline HR for eachvolunteer. Several oral formulations were tested. Each volunteerreceived a formulation orally 3 times daily at 7:00, 15:00, and 22:00;and each time 2 capsules were taken. The dosing range was in the middleof Table 2 above. The medication was administered to each volunteer for3 consecutive days. The HR was measured at the same time points as forthe base-line HR record. Then the average HR of each volunteer subjectwas calculated and recorded. To avoid carry-over medication interferenceor influence on the next medication, both volunteer subjects waited 7days without any medication after completing each type of formulation.The results are summarized in Tables 3 to 5 below.

TABLE 2 4-API Compositions Low Dose Middle Dose High Dose API (mg) (mg)(mg) Theophylline (or an isotopic  3.2-28.8 28.8-80 80-192 variantthereof) (API-1) Nifedipine (or an isotopic 0.16-2.88 1.44-12  4-38.4variant thereof) (API-2) Betahistine (HCl)₂ (or an  0.4-10.8  3.6-4010-120 isotopic variant thereof) (API-3) Levalbuterol HCl (or anisotopic 0.03-1.08  0.27-3.8 0.75-9    variant thereof) (API-4)

TABLE 3 Baseline Heart Rates of Healthy Volunteer Subjects Daily Subject1 Subject 2 HR Average Record (BPM) (BPM) (BPM) First Day 7 am 58 57 6410 am  61 72 6 pm 66 71 Second Day 7 am 56 59 62 10 am  58 72 6 pm 62 65Third Day 7 am 56 57 63 10 am  61 67 6 pm 63 72 HR Average 60 66 63(BPM)

TABLE 4 Heart Rates of Healthy Volunteer Subjects Treated with PlaceboDaily Subject 1 Subject 2 HR Average Record (BPM) (BPM) (BPM) First Day7 am 56 55 60 10 am  61 71 6 pm 59 58 Second Day 7 am 55 57 61 10 am  6060 6 pm 63 69 Third Day 7 am 57 58 62 10 am  60 66 6 pm 61 70 HR Average59 63 61 (BPM)

As shown in Table 4, there was no significant change in heart rate (HR)compared to the baseline measurement of beat per min (BPM) when treatedwith a placebo. However, as shown in above Table 5, the heart rates areincreased 15 BPM for volunteer 1 and 18 BPM for volunteer 2 when treatedwith the 4-API compositions.

Example 9

Cardiovascular Evaluation of 4-API Combinations in Bradycardia Patients

4-API combinations shown in Example 3 were evaluated on bradycardiapatients. The results are summarized in Table 5 below. The bradycardiapatients treated with a 4-API combination experienced disappearance orlessening of symptoms of bradycardia, including chest pains, chesttightness, confusion or memory problems, dizziness, fatigue, shortnessof breach, and syncope.

TABLE 5 Heart Rates of Healthy Volunteer Subjects Treated with theDeveloped Pharmaceutical Composition Daily Subject 1 Subject 2 HRAverage Record (BPM) (BPM) (BPM) First Day 7 am 52 58 73 10 am  85 88 6pm 73 82 Second Day 7 am 68 74 82 10 am  81 98 6 pm 81 90 Third Day 7 am69 75 82 10 am  82 97 6 pm 80 90 HR Average 75 84 79 (BPM)

Example 10

Clinical Evaluation of 4-API Compositions in Symptomatic SinusBradycardia Patients

An open-label, single ascending dose study is conducted to establish thesafety and tolerability of 4-API compositions (shown in Table 2 above)in symptomatic sinus bradycardia patients. Patients with peptic ulcerdisease, seizure disorder, or cardiac arrhythmia are excluded. Patientswith asthma who are taking a beta-agonist and/or theophylline are alsoexcluded.

About 18 patients between 18 to 80 years and with an average heart rateof ≤50 bpm are divided into six cohorts without randomization. Eachcohort has 3-4 symptomatic sinus bradycardia patients. Each patientreceives orally a 4-API composition described in Example 7.

On the day of dosing, the patents are monitored for 2 hours with aHolter monitor to establish a baseline. Immediately after the dosing,the patients are monitored continually with a Holter monitor for atleast 22 hours. A 12-lead electrocardiogram is also taken for eachpatient prior to discharge.

The study starts with the lowest dose. The initial cohort is enrolled ina staggered manner to identify any blood pressure or heart rate effects.Specifically, the study starts with only one patient on the first day ofdosing. If there are no significant adverse events observed in the firstpatient 24 hours after the dosing as monitored by a Holter monitor and12-lead ECG, the second patient is enrolled 24 hours after the firstpatient, and the third patient is enrolled 24 hours after the secondpatient, and so forth. Each patient in a cohort is monitored foradditional 7-days for clinical safety.

Standard clinical evaluation and objective measures are employed tomonitor and assess safety during the study. Safety and tolerabilityassessments for all the patients include adverse events (AEs), physicalexaminations, vital signs (systolic/diastolic blood pressure, heartrate, respiratory rate, and temperature), clinical laboratory tests,digital Holter monitoring Data (ECGs), and local tolerability ratingscales.

If there is little or no effect observed in the first cohort, the doseis increased to the next level. Once effects on heart rate and bloodpressure are observed, the dose is increased in a smaller step to ensurethe dose is safe for the patients. A patient may participate in morethan one dose level study after a ≥7-day washout period. The high doseis designed for atrioventricular block bradycardia patients and may notbe used in this study for sinus bradycardia patients.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the embodiments and are not intended to limit the scope ofthe disclosure. Modifications of the above-described modes for carryingout the disclosure that are obvious to persons of skill in the art areintended to be within the scope of the following claims. Allpublications, patents, and patent applications cited in thisspecification are incorporated herein by reference as if each suchpublication, patent, or patent application were specifically andindividually indicated to be incorporated herein by reference.

We claim:
 1. A method of treating or ameliorating bradycardia in asubject, comprising: administering to the subject in need thereof atherapeutically effective amount of the pharmaceutical compositioncomprising: (i) theophylline or aminophylline 3.2-192 mg/dose; (ii)nifedipine 0.16-38.4 mg/dose; (iii) betahistine 0.4-120 mg/dose; and(iv) levalbuterol or albuterol 0.03-9 mg/dose.
 2. The method of claim 1,further comprising a pharmaceutically acceptable excipient.
 3. Themethod of claim 1, wherein the pharmaceutical composition is formulatedin a dosage form for oral, intravenous, intramuscular administration. 4.A method of treating or ameliorating bradycardia in a subject,comprising: administering to the subject in need thereof a therapeuticeffective amount of the pharmaceutical composition comprising: (a) anythree compounds, wherein each compound is independently (i) theophyllineor aminophylline 3.2-192 mg/dose; (ii) nifedipine 0.16-38.4 mg/dose;(iii) betahistine or a metabolite thereof 0.4-120 mg/dose; and (iv)levalbuterol or albuterol 0.03-9 mg/dose.
 5. The method of claim 4,further comprising a pharmaceutically acceptable excipient.
 6. Themethod of claim 4, wherein the pharmaceutical composition is formulatedin a liquid or solid dosage form for oral, intravenous, intramuscularadministration.
 7. A method of treating or ameliorating bradycardia in asubject, comprising: administering to the subject in need thereof atherapeutic effective amount of the pharmaceutical compositioncomprising: (a) any two compounds, wherein each compound isindependently (i) theophylline or aminophylline 3.2-192 mg/dose; (ii)nifedipine 0.16-38.4 mg/dose; (iii) betahistine or a metabolite thereof0.4-120 mg/dose; and (iv) levalbuterol or albuterol 0.03-9 mg/dose. 8.The method of claim 7, further comprising a pharmaceutically acceptableexcipient.
 9. The method of claim 7, wherein the pharmaceuticalcomposition is formulated in a liquid or solid dosage form for oral,intravenous, intramuscular administration.